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Impact of the Breast Cancer Index on extended endocrine therapy recommendations in patients from the BCI Registry study.
527 Background: The Breast Cancer Index (BCI) test is an established genomic assay that provides individualized risks of overall and late distant recurrence and predicts the benefit from extended endocrine therapy (EET) in patients with early-stage, HR+ breast cancer. Previous findings from the large, prospective BCI Registry have shown that physicians changed their EET recommendation in over 40% of patients following BCI testing. This analysis investigates how physicians integrate prognostic and predictive BCI results in real care settings to decide whether or not to recommend extension of endocrine therapy. Methods: The BCI Registry study (NCT04875351) is evaluating the long-term clinical outcome, decision-impact and medication adherence in about 3000 patients. Pre- and post-BCI physician treatment recommendations were compared using McNemar’s test. Clinicopathologic features of cases were correlated with BCI (H/I) predictive results and post BCI-EET recommendations using Fisher’s exact test. Differences in mean BCI prognostic risk were assessed using analysis of variance (ANOVA). Results: Pre- and post-BCI testing physician questionnaires were completed for 2850 patients. The percentage of patients recommended for EET decreased from 54.6% before BCI testing to 41.2% after BCI testing, while those not recommended for EET increased from 44.9% to 58.0% (p<.0001). Among patients not recommended for EET pre-BCI, physicians cited low risk of recurrence (47.4%), osteoporosis risk (16.7%), side effects (8.6%), or multiple reasons (24.4%). Among BCI (H/I)-High patients (N=1063), recommendations for EET increased from 60.4% pre-BCI to 90.6% post-BCI, while EET non-recommendations decreased from 39.1% to 8.0%. Conversely, in BCI (H/I)-Low patients (N=1787), EET recommendations decreased from 51.1% to 11.8% and EET non-recommendations increased from 48.3% to 87.8%. Post-BCI, BCI (H/I)-High patients who were not recommended EET (8.0%) had more favorable clinicopathological features, including more T1 tumors (83.5% vs. 68.1%, p=.009), more G1 tumors (44.7% vs. 14.4%, p<.0001) and lower mean BCI prognostic risk compared to those for whom EET was recommended (4.4% vs 9.2%, p<.0001). Conversely, BCI (H/I)-Low patients who were recommended EET (11.8%) had a larger proportion of T2/T3 tumors (40.7% vs. 21.7%, p<.0001), more G2/G3 tumors (79.2% vs. 62.8%, p<.0001), more N+(1-3) cases (43.6% vs. 15.7%, p<.0001) and higher mean BCI prognostic risk (8.1% vs 4.7%, p<.0001). Conclusions: BCI results meaningfully inform physician recommendations for EET. Post-BCI, physician EET recommendations increased to 91% in BCI (H/I)-High patients and decreased to 12% in BCI (H/I)-Low patients, highlighting the important treatment guidance provided by BCI. Integration of both predictive and prognostic BCI results help further personalize patient care.
Correlation of an IGF1R RNA activation signature with allostatic load and time to castration resistance in primary prostate cancer patients.
e17026 Background: Insulin-like Growth Factor 1 Receptor (IGF1R) functions as a central mediator of nutrient sensing and energy sufficiency through PI3K–AKT signaling, supporting efficient glucose uptake, mitochondrial function, and redox balance. In primary prostate cancer, activation of IGF1R reflects a metabolically stable tumor state. Conversely, low IGF1R signaling may mark early endocrine uncoupling and metabolic stress adaptation, which increases tumor-derived inflammatory signaling and contributes to heightened cumulative physiological stress in the host. This metabolic stress can be measured by allostatic load, as defined by Guidi et al. (PMID: 32799204). We hypothesized that low IGF1R signaling in primary prostate cancer biopsies is indicative of increased allostatic load, and decreased time to castration resistance (CR). Methods: All prostate cancer patients at UIH who had samples of sufficient quality for RNA sequencing between January 2021 and December 2024 were included in the UIH cohort (n = 104). Retrospective chart review was conducted and RNA sequencing was conducted by Tempus Labs. The IGF1R RNA activation signature (IRAS) was developed using RNA-sequencing data from prostate cancer cell line models (CWR-R1, H660, LASCPC-01, LNCaP p53/Rb KO) treated with IGF alone or in combination with IGF1R inhibitor NVP-ADW742. Differentially regulated (fold-change > 1.2) protein-coding genes above minimum expression threshold (TPM > 0.5) were identified, resulting in a 15-gene IRAS signature that was validated using publicly-available patient data sets. IRAS was assessed against allostatic load and patient outcomes in the UIH cohort. Results: In the UIH patient cohort, allostatic load and time to castration-resistance (CR) were calculated between IRAS-high (n = 42) and IRAS-low (n = 62) primary prostate cancer biopsies. IRAS-high biopsies were associated with lower allostatic load vs. IRAS-low ( p = 0.009), suggesting reduced chronic activation of metabolic stress. IRAS-high patients had significantly higher survival probabilities than IRAS-low ( p = 0.044). After controlling for confounding factors (age, race, ethnicity, BMI, Gleason, stage at diagnosis, de novo metastasis, diabetes diagnosis, and A1C), IRAS-low was significantly associated with increased risk of developing CR on androgen deprivation therapy in both univariate ( p = 0.049) and multivariate ( p = 0.042) Cox Proportional Hazard regression modelling. Conclusions: In this study, we demonstrate that an IGF1R RNA activation signature derived from prostate cancer cell line models is clinically informative in primary prostate cancer and captures a biologically meaningful axis linking tumor metabolism, systemic physiological stress, and therapeutic outcomes.
Dexamethasone reduction or omission with NEPA and olanzapine for HEC: A phase III trial.
12000 Background: Prolonged dexamethasone (DEX) in antiemetic regimens for highly emetogenic chemotherapy (HEC) may impair immunotherapy efficacy. We evaluated if DEX can be reduced or omitted when combined with NEPA (netupitant/palonosetron) and olanzapine without compromising control. Methods: In this open-label, multicenter, phase III non-inferiority trial, adults receiving HEC were randomized 1:1:1 to: Standard Regimen (NEPA day1, olanzapine days1-4, DEX 12mg day1/8mg days2-4); DEX-sparing Regimen (same, DEX 6mg day1 only); or DEX-free Regimen (same, no DEX). The primary endpoint was overall complete response (CR: no emesis/no rescue) 0-120h. A hierarchical testing sequence (DEX-sparing vs Standard, then DEX-free vs Standard) with a -12% non-inferiority margin controlled type I error (one-sided α=0.025). Results: Among 644 randomized patients (median age 54.9 years; 66.9% female), the overall CR rates were 72.4% for Standard, 72.2% for DEX-sparing (rate difference [RD] -0.19%, 95% CI -8.77 to 8.38; P for non-inferiority = 0.004), and 70.1% for DEX-free (RD -2.24%, 95% CI -10.81 to 6.38; P for non-inferiority = 0.013). Both experimental regimens met the non-inferiority criterion. Acute-phase (0-24 h) CR rates were 81.5%, 82.6%, and 80.8% (intergroup comparison, P＞0.05), and delayed-phase (24-120 h) CR rates were 77.1%, 77.6%, and 73.9% ((P＞0.05), respectively, with no significant differences. For complete nausea control, the DEX-free regimen was inferior beyond 24 hours, whereas the DEX-sparing regimen remained comparable to Standard throughout. Steroid-related adverse events, such as insomnia, were primarily reported in the Standard regimen group. Conclusions: NEPA plus olanzapine with single-day low-dose or no DEX is non-inferior to standard 4-day DEX for CINV prevention in HEC, supporting steroid-sparing strategies relevant for chemo-immunotherapy. Clinical trial information: NCT06331520 . Baseline patient characteristics and chemotherapy regimen. Total(N=644） Standard Regimen(N=217) DEX-sparing Regimen(N=213) DEX-free Regimen(N=214) Age, years 54.9 ±12.0 54.2 ±11.7 55.2±12.0 55.3 ±12.2 Male 219 (34.0) 73 (33.6) 74 (34.7) 72 (33.6) Female 425 (66.0) 144 (66.4) 139 (65.2) 142 (66.4) Breast cancer 280 (43.5) 101 (46.5) 92 (43.2) 87 (40.6) Lung cancer 141 (21.9) 45 (20.7) 50 (23.5) 46 (21.5) AC regimen 148 (23.0) 57 (26.3) 52 (24.4) 39 (18.2) Platinum-based regimen 472 (73.3) 153 (70.5) 152 (71.4) 167 (78.0)
Early-onset chronic and metabolic morbidity among survivors of childhood acute lymphoblastic leukemia: Evidence from Middle Eastern real-world data.
10049 Background: Survivors of childhood acute lymphoblastic leukemia (ALL) are at increased risk of long-term morbidity; however, limited data describe the early onset of metabolic and chronic conditions in contemporary cohorts or their association with treatment intensity in real-world settings. Existing evidence largely reflects European or North American populations, historical treatment eras, and fragmented healthcare systems. Data from Middle Eastern populations, particularly within a national health insurance framework enabling longitudinal follow-up across childhood and adulthood, are scarce. This study addresses these gaps by evaluating early-onset metabolic and chronic morbidity among childhood ALL survivors treated across multiple therapeutic eras within Israel’s integrated healthcare system. Methods: We conducted a retrospective cohort study using electronic health records from Clalit Health Services, Israel’s largest integrated payer–provider healthcare system. Five-year survivors of childhood ALL (diagnosed <19 years between 1980–2018) were matched 1:6 to cancer-free controls by age and sex. Chronic conditions were ascertained longitudinally using validated diagnosis codes. Multivariable Cox and logistic regression models estimated associations between ALL survivorship and chronic health outcomes. Among survivors, additional analyses examined associations with treatment intensity, treatment protocol era, and cranial radiation exposure (dose-specific). Results: The cohort included 437 childhood ALL survivors and 2,622 matched controls; survivors were 74.6% Jewish, 18.3% Arab, and 7.1% other ethnicities. Compared with controls, ALL survivors had significantly increased risks of central nervous system conditions (HR 3.65, 95% CI 1.71–7.80), thyroid disorders (HR 2.18, 95% CI 1.55–3.05), cardiovascular disease (HR 2.09, 95% CI 1.35–3.22), diabetes (HR 1.83, 95% CI 1.05–3.21), obesity (HR 1.58, 95% CI 1.31–1.91), and metabolic syndrome (OR 2.09, 95% CI 1.53–2.80). No ethnic differences were found across all chronic conditions. Excess morbidity occurred within the first 2-years of survivorship and persisted through 5- years, except for endocrine that became apparent later. Higher treatment intensity, earlier treatment protocols, and hematopoietic stem cells were associated with greater burden. Conclusions: Childhood ALL survivors experience early and disproportionate accumulation of chronic conditions, at young ages. Leveraging real-world data, this study provides novel evidence that treatment intensity and protocol era strongly shape early survivorship risk; unrelated to type of healthcare or ethnicity. These findings highlight the need for early, risk-adapted surveillance and targeted metabolic prevention strategies in contemporary ALL survivorship.
Digital information–seeking behavior in patients with cancer through storytelling.
9044 Background: Peer support for cancer patients through narrative interventions can have benefits for quality of life, emotional health, and self-efficacy. This support has classically been provided through static text content on websites, but less is known on whether video-based platforms can preferentially drive patient engagement and self-activation. The Patient Story is a multi-channel platform specializing in video-focused patient-led programs and stories designed to reduce emotional burden and drive patient self-advocacy that leads to informed treatment decision-making. We sought to describe engagement between webpage delivery and a video-based version to understand how different digital platforms could drive varying levels of patient reach and activation, including measurable behavioral changes like motivation to ask doctors questions about treatment and care. Methods: Site traffic data relative to benchmarks and participant characteristics visiting The Patient Story were prospectively collected (1/1/22–12/31/25) using Google Analytics 4 for the website and YouTube Studio for the videos. A retrospective review was done on a convenience sample of 4,065 digital platform viewers who then participated in high-touch educational webinars led by patient moderators and multidisciplinary health care providers. Impact was assessed via post-program surveys (n=1,452; 36% response rate) measuring shifts in treatment awareness and behavioral intent. Results: A higher percentage of patients who viewed the video platform were female (72.9%) compared to the website (64.4%). Video platform participants tended to be older, with 24% 65+ years old compared to 13% of web participants. Mobile devices were most commonly used for websites (71.2%) and video (54.8%) while 24.8% of those who engaged on video platforms used SmartTV. Reach was substantially higher with the video platform, which generated 72.4M views (average duration on video 6:04) compared to 1.8M website views (89.7% engagement rate). Significant shifts were observed: treatment awareness increased from 3.6 to 4.2 (on a 5-pt scale), and 51.5% of respondents reported a specific intent to discuss the webinar topics (treatment and clinical trial education) with their physician. Conclusions: Video first-person storytelling is a novel way of helping patients receive peer support and information. Cancer patients increasingly seek information through mobile and video platforms rather than traditional web searches on desktop computers. Health systems should consider multiple methods of digital communication to increase patient engagement. Metric Value (N=1,452) Topic Pre-Awareness (5pt scale) 3.6 Topic Post-Awareness (5pt scale) 4.2 % Change in Awareness +16.7% Intent to Discuss with Doctor 51.5% Intent to Research Clinical Trials 20.1%
Disparities in utilization of genomic risk assays in early-stage hormone-positive breast cancer: A retrospective analysis using National Cancer Database (NCDB).
537 Background: Prognostic genomic assays (GA) have become crucial in the management of early-stage hormone receptor positive breast cancer, particularly in guiding adjuvant chemotherapy decisions. Despite this, GA remain underutilized. This study aimed to identify predictors of GA utilization and associated survival outcomes. Methods: The 2023 NCDB PUF dataset was used to identify patients aged ≥ 18 years with HR positive, HER2 negative breast cancer diagnosed between 2010-2023. Patients with T1-T4, N0-N1 disease who underwent surgical resection were included, while those with T1aN0 stage, M1 disease, unknown GA status, or receipt of BCI alone were excluded. Patients were stratified by the receipt of the GA. Descriptive and multivariable analyses were performed to identify factors associated with GA utilization, and survival was assessed using Kaplan-Meier (KM) analysis. Results: 594,872 patients were included in our study, of whom 63.12% (N=375,506) underwent GA testing. GA utilization increased over time from 52.7% in 2010-2015 period to 68.7% in 2021-2023 (p<0.001). Using multivariable analysis, higher odds of GA testing were seen among Whites vs Blacks (OR 1.13 (1.11-1.16)), those with T2 tumors vs T1 (OR 1.26 95% CI 1.24-1.27), Grade 2 (OR 1.49 (1.47-1.51) or Grade 3 (1.42 (1.39-1.45)) histology vs Grade 1, receiving regional lymph node surgery vs not (OR 2.47 (2.33-2.62)), hormonal therapy vs not (OR 2.39 (2.34-2.43)), radiation vs not (OR 1.32 (1.30-1.34)), and recent year of diagnosis, 2021+ vs 2010-2015 (OR 2.08 (1.99-2.18)). The odds of GA testing were lower for uninsured vs government insured patients (OR 0.86 (0.82-0.91)), those with higher T stages (T3: OR 0.63 (0.61-0.65) and T4: OR 0.26 (0.24-0.30)) vs T1, N1 disease vs N0 (OR 0.73 (0.72-0.74)) and increasing age with the lowest odds among patients aged>80 (OR 0.13 (0.13-0.14)) compared to 18-64 years old. KM analysis showed survival benefit favoring receipt of GA (HR= 0.4 (0.39-0.41), p<0.001). Conclusions: Our study portrays low utilization of GA despite increasing use over time reflecting the impact of the TAILORx and RxPONDER trials. Significant disparities persisted by age, insurance status, race, and tumor characteristics. Older, Black and uninsured patients were substantially less likely to receive testing, despite an associated survival benefit, underscoring the need for more equitable implementation of guideline-recommended GA.
Impact of radiologically identified embryological origin on recurrence patterns and survival in resectable pancreatic head adenocarcinoma.
4228 Background: The pancreatic head develops embryologically from the fusion of the dorsal pancreatic (Dp) and ventral pancreatic (Vp) buds, which differ in cellular composition. Although histopathology is considered the gold standard for distinguishing these structures, they can also be differentiated radiologically. The prognostic significance of the embryological origin of pancreatic head adenocarcinomas remains unknown. This study aimed to investigate the impact of tumor embryological location on survival outcomes in patients with resectable pancreatic head adenocarcinoma. Methods: Patients who underwent surgical resection for pancreatic head adenocarcinoma were retrospectively analyzed. Preoperative conmputed tomography images were used to determine the embryological tumor location. The boundary between Dp and Vp was defined as a line connecting the portal vein/superior mesenteric vein to the anterior margin of the intrapancreatic bile duct. Tumors located predominantly (≥80%) on one side of this boundary were classified accordingly, while tumors without ≥80% predominance in either region were classified as mixed. Patients were grouped as Vp, Dp, or mixed pancreatic (Mp) origin. The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). Results: A total of 164 patients were included. Tumor origin was classified as Vp in 74 patients (45.1%), Dp in 63 patients (38.4%), and Mp in 27 patients (16.5%). Mp tumors were associated with a significantly higher rate of grade 3 tumors (48.1% in Mp vs 21.6% in Vp and 23.8% in Dp, p = 0.005) and advanced T stage (T3–T4: 70.3% in Mp vs 32.4% in Vp and 47.6% in Dp, p = 0.009). Other baseline clinicopathological characteristics, and the rates of adjuvant chemotherapy and radiotherapy were similar among groups. Median PFS was 11.2 months (95% CI 10.5–11.9) in Mp, 13.0 months (95% CI 9.3–16.7) in Vp, and 9.8 months (95% CI 7.6–11.9) in Dp (p = 0.032). All recurrences in the Dp group were distant metastases, whereas Mp tumors recurred predominantly as distant metastases (85.7%) and Vp tumors showed a higher proportion of local recurrence (33.3%) (p < 0.001). Median OS was significantly longer in the Vp group (Mp: 16.7 months, 95% CI 8.9–27.4; Vp: 25.3 months, 95% CI 11.8–37.8; Dp: 16.7 months, 95% CI 13.2–20.3; p = 0.006). Conclusions: The embryological origin of pancreatic head adenocarcinoma is associated with distinct pathological features, survival outcomes, and recurrence sites. Vp-origin tumors demonstrate superior OS but higher local recurrence rates, whereas Dp-origin tumors are characterized by early distant metastasis. Preoperative CT-based identification of tumor origin serves as a non-invasive prognostic tool that may guide personalized adjuvant strategies, such as intensifying systemic therapy for Dp/Mp tumors or optimizing local control for Vp tumors.
Stage-specific comparative effectiveness of locoregional therapies in early-stage hepatocellular carcinoma: A global real-world analysis.
e16277 Background: Locoregional therapies are central to the management of early-stage hepatocellular carcinoma (HCC) in patients who are not candidates for surgical resection. Transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and thermal ablation (radiofrequency or microwave ablation; RFA/MWA) are widely used, yet comparative, stage-specific real-world effectiveness data remain limited. Methods: We conducted a retrospective comparative effectiveness analysis using the TriNetX global research network. Adults with early-stage HCC treated with TACE, TARE, or ablation as first locoregional therapy were stratified by tumor stage (T1 vs T2). Propensity score matching was performed within each head-to-head comparison to balance demographics, liver disease severity, comorbidities, and baseline characteristics. Overall survival (OS) was the primary endpoint. Results: T1 tumors: After matching, 224 patients per group were included for TACE versus TARE. Three-year OS was significantly lower with TACE compared with TARE (62% vs 75%, p = 0.0076). Ablation versus TACE included 236 patients per group, with 1-year OS of 89% versus 83% ( p = 0.0595) and 3-year OS of 69% versus 63% ( p = 0.1063). Ablation versus TARE included 233 patients per group, with 1-year OS of 90% versus 89% ( p = 0.7288) and 3-year OS of 69% versus 71% ( p = 0.7925). T2 tumors: After matching, 157 patients per group were analyzed for TACE versus TARE, with 3-year OS of 59% versus 66% ( p = 0.0579). Ablation versus TACE included 108 patients per group (1-year OS 86% vs 89%; p = 0.6608; 3-year OS 57% vs 58%; p = 0.7989). Ablation versus TARE included 114 patients per group (1-year OS 85% vs 80%; p = 0.3342; 3-year OS 59% vs 58%; p = 0.2089). Conclusions: In T1 HCC, stage-specific survival differences were observed, with TARE and ablation demonstrating superior survival compared with TACE and no significant difference between TARE and ablation. No survival differences were identified among T2 patients, likely reflecting limited statistical power due to smaller sample sizes. Larger prospective studies are needed to more definitively compare survival outcomes of locoregional therapies across disease stages.
Acute care events after outpatient systemic therapy among patients at elevated risk for acute care utilization.
e23246 Background: A subset of acute care events (ACE) within 30 days of outpatientsystemic therapy is potentially preventable and is tracked under CMS qualitymeasure OP-35. It remains unclear whether baseline data alone can predict thesepreventable events (PACE30). We evaluated prediction of PACE30 and examined itsdistribution within the broader population at risk for any ACE30. Methods: We studied 12,231 patients receiving initial outpatient systemic therapy(cytotoxic, immunotherapy, targeted, and endocrine regimens) at a large cancer center(2012–2021). ACE30 and PACE30 were identified using CMS OP-35–alignedstandardized definitions. Baseline predictors included demographics, disease andtreatment characteristics, laboratory values, vital signs, and pre-treatment healthcareutilization. We developed standalone models to predict PACE30. For context, weapplied a previously developed 56-variable L1-regularized logistic regression model(internally developed and benchmarked against published PROACCT models) to stratifyACE30 risk. We assessed PACE30 enrichment among ACE30 high-risk patients andtested whether two-stage (conditional) modeling within high-risk strata improvedPACE30 discrimination. Model performance was assessed via AUC, positive predictivevalue (PPV), and risk enrichment at fixed capacity thresholds. Results: ACE30 occurred in 22.9% of patients, and PACE30 occurred in 4.5% (~20%of all ACE30). Standalone baseline models showed modest discrimination for PACE30(AUC 0.62, PPV 0.10) compared with stronger performance for ACE30 (AUC 0.68, PPV0.47). Conditional modeling restricted to the top 20% of ACE30 risk did not meaningfullyenhance PACE30 discrimination or stratification. However, the top 20% ACE30 riskgroup exhibited nearly twofold higher PACE30 rates (8.2% vs 4.5% overall),demonstrating substantial enrichment of preventable events among patients withelevated baseline clinical instability and acute care risk. Conclusions: Baseline pre-treatment variables offer limited direct predictive power todistinguish preventable from non-preventable acute care events after systemic therapyinitiation, even within high-risk subgroups. Nevertheless, preventable events clusterdisproportionately in patients identified as high-risk for any acute care utilization viabaseline stratification. Preventability appears driven predominantly by downstream post-systemic therapy care delivery processes rather than pre-treatment patientcharacteristics. Efforts to reduce avoidable acute care should prioritize targeted post-systemic therapy interventions—including proactive symptom monitoring, rapid access pathways, and enhanced care coordination—focused on patients identified as high-riskby baseline models, rather than relying solely on direct baseline prediction ofpreventability.
Prognostic performance of Child-Pugh and MELD scores in critically ill patients with hepatocellular carcinoma: A MIMIC-IV cohort study.
e16235 Background: Hepatocellular carcinoma predominantly arises in cirrhotic patients, creating dual disease burden that complicates intensive care unit (ICU) prognostication. We evaluated the comparative performance of liver-specific prognostic scores in predicting ICU mortality among HCC patients. Methods: This retrospective cohort study utilized the MIMIC-IV database (2008-2022) to identify adult HCC patients admitted to ICU. We calculated Child-Pugh scores and Model for End-Stage Liver Disease (MELD) scores from admission laboratory values. Primary outcome was hospital mortality. We performed multivariable logistic regression to identify independent mortality predictors and compared prognostic discrimination using area under the receiver operating characteristic curve (AUROC). Results: Among 1,771 HCC patients, 698 (39.4%) had cirrhosis. Paradoxically, cirrhotic patients demonstrated lower mortality than non-cirrhotic patients (6.4% vs 8.9%). Among cirrhotic patients, Child-Pugh class stratified mortality risk: class A 2.3%, class B 6.4%, class C 14.8% (p < 0.001). Child-Pugh score showed superior discrimination compared to MELD (AUC 0.702 vs 0.644). Independent mortality predictors included age (OR 1.04, 95% CI 1.01-1.08), MELD score (OR 1.06, 95% CI 1.02-1.10), and vasopressor use (OR 8.54, 95% CI 3.45-21.14). Vasopressor requirement demonstrated the strongest mortality association, exceeding liver dysfunction severity. A combined liver-ICU prognostic score provided only marginal improvement over Child-Pugh alone (AUC 0.707 vs 0.702). Conclusions: In critically ill HCC patients, Child-Pugh score outperforms MELD for short-term mortality prediction, likely reflecting its capture of acute hepatic decompensation. Vasopressor requirement dominates prognostic importance, emphasizing that hemodynamic failure supersedes chronic liver disease severity in ICU settings.
Clinical characteristics of patients with metastatic uveal melanoma and assessment of long-term survivors.
e21509 Background: Metastatic uveal melanoma (MUM) is a rare malignancy with poor prognosis and limited systemic treatment options. This study evaluates prognostic factors and treatment outcomes in patients with MUM managed at a tertiary reference center. Methods: 91 patients with MUM treated between 2012 and 2025 were evaluated. Demographic, and clinical data were collected. Survival was analyzed using Kaplan–Meier and Cox regression models. Results: Among 91 patients, 46 (50.5%) were male, with a median age of 61 years. Most of the patients had metachronous metastases (91%) and median disease-free interval (DFI) was 32 months. Liver metastases were identified in 95%. Immunotherapy (IO) was used in 67 (74%) patients, including 14 patients in the first-line setting. IO achieved an ORR of 7% and a disease control rate of 64%. Tebentafusp was not available in our country. Locoregional therapies (LT) were administered in 56%. Median overall survival (OS) for the entire cohort was 16.6 months (95% CI, 13.1–20.1). On multivariate Cox regression analysis, female sex, longer DFI (>36 months), lower baseline AST levels, and receipt of LT were independently associated with improved OS. Patients who received combined IO (anti-PD1 plus anti-CTLA4; n=21) had a trend towards longer OS compared to those who received single agent IO (anti-PD1 alone or anti-CTLA4 alone; n=46) as initial IO regimen (HR 0.51; 95%CI 0.26-0.99, p=0.049). 30 patients (33%) survived more than 24 months following the diagnosis of metastatic disease. 97% of these patients had metachronous metastases, 67% had DFI >36 months, 60% had liver directed LT, 67% were females and 70% had undergone enucleation as the primary treatment. Conclusions: This real-world study showed modest efficacy of IO in the treatment of MUM. Combination IO demonstrated a trend toward improved OS compared to mono-IO. Liver directed LT appeared to provide the greatest benefit. Long DFI in patients with metachronous metastatic disease, female sex, and normal transaminase levels are other prognostic factors associated with improved OS. Univariate and multivariate Cox regression analysis for overall survival. Variables Univariate HR (95% CI) Univariate p value Multivariate HR (95% CI) Multivariate p value Female (ref: male) 0.47 (0.29–0.77) 0.003 0.43 (0.24–0.79) 0.007 DFI ≤ 36 mo (ref: >36 mo) 2.28 (1.40–3.70) <0.001 2.30 (1.21–4.35) 0.011 Locoregional therapy: Yes (ref: No) 0.35 (0.22–0.58) <0.001 0.32 (0.17–0.57) <0.001 AST >ULN (ref: ≤ULN) 2.85 (1.56–5.21) <0.001 2.78 (1.27–6.09) 0.01 ALP >ULN (ref: ≤ULN) 2.30 (1.27–4.15) 0.006 1.44 (0.57–3.63) 0.43 LDH >ULN (ref: ≤ULN) 2.08 (1.24–3.50) 0.005 1.49 (0.83–2.65) 0.17 Any-line immunotherapy: Yes (ref: No) 0.56 (0.34–0.93) 0.026 1.04 (0.43–2.55) 0.92 ALP: Alkaline phosphatase, AST: Aspartate aminotransferase, DFI: Disease-free interval, HR: Hazard ratio, LDH: Lactate dehydrogenase, ref: Reference, ULN: Upper limit normal.
Dermatologic adverse events (dAEs) and emotional quality of life (QoL) in patients (pts) with breast cancer: A mixed-methods study.
12076 Background: dAEs are a common and impactful aspect of QoL and have an emotional impact. However, its measurement relating to cancer care is limited. Validated tools focus on dermatology or chemotherapy but can be disconnected. Our pilot study utilized several validated tools to assess overall dAEs and their impact. Methods: Mixed methods consisting of a cross-sectional survey with qualitative interviews was conducted on pts with breast cancer who recently completed (<1 year) chemotherapy (acute) or completed chemotherapy ≥1 year ago (longitudinal). A panel of dermatologic and oncologic patient-reported outcome measures (PROMs) was: PRO Version of the Common Terminology Criteria for AEs (PRO-CTCAE), Skindex-16 (S-16), Fear of Cancer Recurrence–Short Form (FCR-SF), and Impact of Events–Intrusive Thoughts subscale (IES). Semi-structured interviews were done to elicit responsiveness to this panel. Results: 64 pts were screened & 60 enrolled (mean age: 63.0±19.1). Pts were Female and insured (100%), White (78.3%) & Black (20%). Pts were treated with radiation (70%), surgery (66.7%), hormone therapies (23%), targeted or immunotherapies (15%). Common symptoms were xerosis (73.3%), alopecia (66.7%), pruritus (58.3%). Mean total S-16 score was 19.4 (range: 0 (no impact) to 75.5 (most impact)); PRO-CTCAE 22.2 (0, 48.5); FCR-SF 43.2 (0, 97.2); IES 20.8 (0, 65.6). S-16 scores demonstrated moderate correlations with PRO-CTCAE (r=0.60, CI=0.41-0.74, p<0.001), indicating related but nonredundant constructs. The S-16 didn’t correlate with the FCR-SF or IES, suggesting distinct emotional burdens on pts with cancer. There was no significant difference in survey scores between acute and longitudinal groups. Qualitative analyses revealed this combination of surveys encapsulated QoL and emotional experiences related to dAEs. Several pts were unaware of the dAEs they could experience as well as how to treat them. Conclusions: This is a novel assessment of dAEs in QoL, implementing and comparing cancer-specific PROMs to common dermatologic PROMs. Results indicate that dAEs significantly impact QoL and oncological psychometric outcomes are not fully captured with current dermatologic PROMs. Correlations between PROM scores. Instrument Pair Correlation (r) 95% CI P-value PRO-CTCAE total S-16 total S-16 symptoms S-16 emotional S-16 functioning 0.600.650.480.40 0.41 to 0.740.48 to 0.780.26 to 0.660.17 to 0.60` <.001<.001<.0010.001 FCR-SF total S-16 total S-16 symptoms S-16 emotional S-16 functioning PRO-CTCAE total IES total -0.15-0.08-0.17-0.14-0.060.06 -0.39 to 0.11-0.32 to 0.18-0.40 to 0.09-0.38 to 0.12-0.31 to 0.20-0.20 to 0.31 0.2520.5620.2070.2950.6460.657 IES total S-16 total S-16 symptoms S-16 emotional S-16 functioning PRO-CTCAE total 0.14-0.030.190.190.24 -0.12 to 0.38-0.28 to 0.23-0.07 to 0.42-0.07 to 0.42-0.01 to 0.47 0.2870.8450.1480.1420.062
Real-world outcomes in <i>EGFR</i> subtypes and co- <i>TP53</i> mutations in metastatic non-small cell lung cancer.
e20705 Background: EGFR mutations are key oncogenic drivers in non–small cell lung cancer (NSCLC) and predict response to EGFR tyrosine kinase inhibitors (TKIs). Despite therapeutic advances, outcomes vary by EGFR subtype, like exon 19 deletions and L858R substitutions, and co-mutations, like TP53 . However, the prognostic impact of these molecular features across generations of TKIs in real-world practice remains unclear. We investigated the impact of EGFR subtype and TP53 co-mutation on clinical outcomes within a real-world metastatic EGFR -mutant NSCLC cohort. Methods: We performed a retrospective study via chart review of patients with metastatic EGFR -mutant lung cancer treated within Northwell Health from 2018-2024. Clinical, demographic, molecular, and treatment data were collected. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan–Meier methods and compared by EGFR subtype ( exon 19 vs L858R ) and TP53 status using log-rank tests and Cox models. Results: Among the 185 patients within the cohort, 67% were female and never-smokers, with a median age of 69 years (IQR 60–78). Most presented with de novo stage IV disease (75%) and ECOG 0–1 (80%). EGFR alterations included exon 19 deletions (56%), L858R (28%), and atypical mutations (14%); TP53 co-mutation was present in 52%. Common metastatic sites were lung (88%), pleura (30%), bone (35%), brain (32%), and liver (13%). Metastatic distribution was largely comparable between exon 19 to L858R , though L858R was associated with higher rates of bone (47% vs 31%) and adrenal (11% vs 6%) involvement. At 3 months, 72% achieved a response, 17% had stable disease, and 11% experienced progression. At data cut-off, 83% had progressed and 44% had died. Median PFS did not differ between exon 19 and L858R (17.3 vs 15.3 months, p=0.48) or TP53 status (19.8 vs 15.2 months, p=0.09). Median OS was significantly longer with exon 19 versus L858R (62.8 vs 35.9 months, p<0.01) and for TP53 -mutant vs wild-type (29.7 vs 61.8 months, p<0.01) (Table 1). Conclusions: This study examined EGFR mutation subtype and TP53 co-mutation in a real-world metastatic EGFR -mutant NSCLC cohort across multiple TKI generations. While PFS did not differ significantly, OS was significantly longer in patients with exon 19 deletions compared with L858R mutations and in those without TP53 co-mutation. Sites of metastases between EGFR subtle were roughly even in distribution. These findings highlight the stability of EGFR subtype and TP53 -associated prognostic signals despite evolving therapeutic landscapes in metastatic EGFR -mutant NSCLC. Survival outcomes in EGFR -mutant metastatic NSCLC. EGFR Subtype Co-Mutation L858R (months) Exon 19 (months) P-value HR (95% CI) TP53 (months) Non- TP53 (months) P-value HR (95% CI) PFS 15.3 17.3 0.48 1.15 (0.78-1.70) 15.2 19.8 0.09 1.36 (0.96-1.94) OS 35.9 62.8 <0.01 2.07 (1.22-3.54) 29.7 61.8 <0.01 2.19 (1.32-3.63)
Malignant pericardial effusion: A high-risk marker for in-hospital mortality and cardiovascular collapse in cancer patients.
e24032 Background: Malignant pericardial effusion (MPE) is a known complication of advanced malignancy and may reflect aggressive tumor biology or acute hemodynamic compromise However, its independent association with in-hospital mortality across major cancer types remains incompletely defined. We evaluated whether MPE predicts in-hospital mortality and adverse outcomes among patients hospitalized with malignancy. Methods: We conducted a retrospective cohort study using the National Inpatient Sample (NIS). Adult hospitalizations with a primary admission diagnosis of lung cancer, breast cancer, or lymphoma were identified and stratified based on the presence of malignant pericardial effusion using ICD-10 code I31.31. The primary outcome was in-hospital mortality. Secondary outcomes included length of stay (LOS), cardiac tamponade, and cardiogenic shock. Multivariable logistic and linear regression models were used to adjust for demographics and comorbidity burden. Adjusted odds ratios (aORs) and adjusted mean differences are reported. Results: A total of 5,388,493 hospitalizations were included, of which 1,005 (0.01%) had malignant pericardial effusion. The cohort comprised lung cancer (51.6%), lymphoma (27.1%), and breast cancer (22.0%). Patients with MPE were younger (mean age 62.3 vs 67.0 years, p < 0.001), more often female (63.2% vs 58.1%), and had a higher proportion of Hispanic and Asian patients (p < 0.001). Overall in-hospital mortality was 7.0%. Mortality was significantly higher among patients with MPE compared with those without (12.4% vs 7.0%, p < 0.001). After multivariable adjustment, MPE remained independently associated with increased in-hospital mortality (aOR 1.88, p = 0.004). Mean LOS was longer in the MPE group (8.9 vs 6.1 days), corresponding to an adjusted increase of 2.47 days (p < 0.001). Additionally, MPE was strongly associated with cardiac tamponade (aOR 158.2, p < 0.001) and cardiogenic shock (aOR 4.40, p < 0.001). Conclusions: Among patients hospitalized with lung cancer, breast cancer, or lymphoma, malignant pericardial effusion is independently associated with significantly higher in-hospital mortality, prolonged length of stay, and severe cardiovascular complications. These findings highlight MPE as a high-risk clinical marker that may warrant early recognition and heightened inpatient monitoring.
Real-world data from the TriNetX database comparing abiraterone versus darolutamide in hormone-sensitive prostate cancer.
e17092 Background: Abiraterone and darolutamide are among several novel androgen receptor pathway inhibitors (ARPIs) that have demonstrated improved survival outcomes when added to androgen deprivation therapy (ADT) in patients with hormone-sensitive prostate cancer (HSPC). Despite their established efficacy, there are currently no high-level evidence data directly comparing abiraterone and darolutamide when combined with ADT prior to the initiation of chemotherapy. Methods: We conducted a retrospective cohort study using the TriNetX database to identify adult patients (≥18 years) with HSPC defined using ICD-10 diagnosis codes. After propensity score matching to balance baseline characteristics, each of the abiraterone and darolutamide cohorts included 363 patients. Prior exposure to docetaxel was excluded from both cohorts. The primary outcomes were the percentage of patients who developed hormone-resistant disease and overall survival. Comparative outcome analyses were performed, and overall survival was evaluated using Kaplan–Meier analysis. Results: The mean age at diagnosis was 73 years. The majority of patients were White 73%, while 19% were Black or African American. The percentage of patients developing hormone-resistant disease was significantly higher in the abiraterone group compared with the darolutamide group (23.8% vs 9.1%, p < 0.0001; OR 3.1; 95% CI, 1.9–5.0). Kaplan–Meier survival analysis demonstrated significantly worse overall survival in patients treated with abiraterone compared with those treated with darolutamide. All-cause mortality was also higher in the abiraterone group (OR 3.4; 95% CI, 2.3–5.1). During follow-up, median overall survival was 60 months in the abiraterone group, while median survival was not reached in the darolutamide group. The difference was statistically significant and treatment with abiraterone was associated with a higher risk of death (log-rank p = 0.006; HR 1.65; 95% CI, 1.14–2.37). Conclusions: In this real-world analysis of patients with HSPC treated with ADT plus an ARPI prior to chemotherapy, darolutamide was associated with lower rates of developing hormone-resistant disease and improved overall survival compared to abiraterone. These findings suggest meaningful differences in outcomes between ARPIs in the pre-chemotherapy setting, however, confirmation in prospective comparative studies is warranted.
Impact of inulin on immunotherapy efficacy in extensive-stage small cell lung cancer and on promotion of CD8+ T-cell tumor infiltration and functional activity.
e20145 Background: Response to immune checkpoint inhibitor (ICI)–based therapy in extensive-stage small cell lung cancer (ES-SCLC) is highly heterogeneous, and robust predictive biomarkers remain scarce. Growing evidence suggests that gut microbiota-derived metabolites regulate systemic antitumor immunity by modulating CD8+ T cell function. Inulin, a dietary prebiotic, can reshape gut microbial composition, but its role in ES-SCLC immunotherapy has not been fully elucidated. This study investigated whether Inulin enhances immunotherapy efficacy in ES-SCLC through modulation of the gut microbiota-metabolite-CD8+ T cell axis. Methods: A retrospective cohort study was conducted on patients with ES-SCLC who received first-line treatment with PD-1 inhibitor. The patients were grouped based on the baseline peripheral blood CD8+ T cell level. The high group consisted of 9 patients and the low group of 15 patients. The progression-free survival (PFS) of the two groups was analyzed. Baseline fecal samples underwent metagenomic sequencing and untargeted metabolomics to characterize gut microbial and metabolic features associated with therapeutic outcomes. A SCLC mouse model was used to evaluate the antitumor effects of Inulin, anti-PD-1 therapy, and their combination. Tumor growth, immune infiltration, and cytokine production were assessed by flow cytometry and ELISA. In vitro assays examined the direct effects of Inulin on tumor cells and CD8+ T cell function. Results: Patients with higher baseline CD8+ T cell levels exhibited significantly prolonged PFS following immunotherapy. Distinct gut microbial profiles were observed between patients with favorable and poor responses. Metabolomic analysis revealed higher fecal Inulin levels in patients with elevated CD8+ T cell levels, and Inulin demonstrated predictive value for immunotherapy benefit. In vivo, Inulin significantly enhanced the antitumor efficacy of anti-PD-1 therapy, accompanied by increased tumor-infiltrating CD8+ T cells and elevated IFN-γ, TNF-α, and granzyme B production. In vitro experiments showed that Inulin had no direct cytotoxic effects on tumor cells but augmented CD8+ T cell effector function. Conclusions: Immunotherapy efficacy in ES-SCLC is closely linked to gut microbiota composition and metabolic features. Inulin enhances CD8+ T cell-mediated antitumor immunity through modulation of the gut microenvironment and synergizes with anti-PD-1 therapy, supporting its potential as both an adjunctive therapeutic strategy and a candidate biomarker for immunotherapy responsiveness.
A multi-axis biomarker model integrating KIM-1 and MAdCAM-1 in metastatic renal cell carcinoma.
4554 Background: Kidney injury molecule-1 (KIM-1) and mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1) have each emerged as prognostic circulating biomarkers in metastatic renal cell carcinoma (mRCC). Whether these biomarkers capture overlapping or complementary aspects of disease biology, and whether their integration improves risk stratification, remains unclear. Methods: Baseline plasma KIM-1 and MAdCAM-1 levels were measured in 612 patients with previously untreated mRCC from the JAVELIN Renal 101 trial, including 323 patients treated with avelumab + axitinib and 289 with sunitinib. Biomarker concentrations were analyzed as continuous variables after log10 transformation. Associations with overall survival (OS) and progression-free survival (PFS) were assessed using multivariable Cox models adjusted for IMDC risk, age, and sex. A composite KIM-1–MAdCAM-1 risk score was developed to assess the incremental prognostic value of integrating these biomarkers. Results: Both KIM-1 and MAdCAM-1 levels were independently associated with OS and PFS in univariable analyses. In multivariable models including both biomarkers and adjusted for age, sex, and IMDC risk, higher KIM-1 levels remained associated with worse survival (OS: HR 1.57, 95% CI 1.28–1.93), whereas higher MAdCAM-1 levels were associated with improved survival (OS: HR 0.37, 95% CI 0.15–0.92). No significant interaction was observed between KIM-1 and MAdCAM-1, nor between either biomarker and treatment arm for OS or PFS. A composite KIM-1–MAdCAM-1 risk score was strongly associated with clinical outcomes. Patients in the highest-risk quartile had significantly worse PFS (median: 8.3 [5.7–11.1] vs 19.4 [13.8–NR] months) and OS rate (at 18 months: 65.0% [57.3–73.8] vs 90.0% [85.0–95.2]) compared to the lowest-risk quartile, across both treatment arms (Table). A joint KIM-1–MAdCAM-1 model demonstrated improved discrimination compared with either biomarker alone (p < 0.001), and the addition of both biomarkers to IMDC significantly improved OS discrimination (C-index 0.73 vs 0.67; p < 0.001). Conclusions: KIM-1 and MAdCAM-1 provide complementary and non-redundant prognostic information in mRCC. Their integration into a composite risk score significantly improves risk stratification beyond either biomarker alone and beyond IMDC criteria. These findings support a multi-axis circulating biomarker approach to prognostication in mRCC. Association of KIM-1–MAdCAM-1 composite score quartiles with progression-free and overall survival in the overall study cohort and by treatment arm. KIM-1–MAdCAM-1 Composite Score Entire CohortHR (95% CI) Avelumab + AxitinibHR (95% CI) SunitinibHR (95% CI) Progression-Free Survival (Q4 vs Q1) 2.12 (1.56–2.87) 2.00 (1.31–3.05) 2.20 (1.41–3.43) Overall Survival (Q4 vs Q1) 4.67 (2.71–8.05) 3.61 (1.75–7.44) 5.89 (2.54–13.7) HR, hazard ratio; CI, confidence interval; Q, quartile.
Clinicopathological characteristics, treatment patterns, and contrast-enhanced computed tomography surveillance in post-treated breast cancer patients: A single-center study from Nepal.
e13626 Background: Breast cancer is a leading malignancy in Nepal. While mammography is the surveillance standard, its sensitivity is limited by dense tissue or post-treatment changes. Evidence on the role of contrast-enhanced computed tomography (CECT) for post-treatment follow-up in resource-constrained settings is sparse. This study evaluates clinical characteristics, treatment patterns, and the utility of CECT-based surveillance in identifying recurrence at a tertiary center. Methods: A retrospective study included 258 post-treated patients undergoing CECT follow-up at BP Koirala Memorial Cancer Hospital (July 2023–January 2024). Data analyzed included histopathology, AJCC 8th edition staging, and IHC (ER, PR, HER2). Variables included chemotherapy, surgery type, and radiotherapy. CECT was used to identify locoregional and distant metastasis patterns. Survival was calculated from the date of surgery. Statistical analysis (SPSS v25.0) utilized descriptive measures and Fisher’s exact test to compare recurrence rates between major chemotherapy regimens. Results: Mean age was 48.3±11.1 years; 60.5% were aged 41–60. Invasive carcinoma NST (82.1%) and triple-negative disease (32.8%) predominated. Most patients presented at stage IIA (34%) or IIIA (25%). Modified radical mastectomy was the primary surgery (91.9%), with a 20% recurrence rate. CECT identified recurrence or metastasis in 21.8% (n = 54). Primary metastatic sites were lymph nodes (59.3%), bone (29.6%), lung (20.4%), and liver (18.5%). Median survival (MS) for the overall cohort was 594 days (IQR 847). Stage-specific MS: IA 660d (IQR 979.75), IIA 662d (IQR 1167.25), IIIA 641d (IQR 714), and IIIC 668.5d (IQR 941.5). Anthracycline/taxane-based (AC-T) regimens (51.4%) and FEC (28.0%) were most frequent. No significant difference in recurrence was observed between AC-T (17.6%) and FEC (13.2%) (p = 0.54). Imaging also identified pulmonary fibrosis (10.5%) and non-neoplastic skin thickening (8.1%). Conclusions: CECT detected significant locoregional and distant recurrence in asymptomatic patients, supporting its role as a complementary tool where locally advanced disease and triple-negative subtypes prevail. Risk-adapted surveillance with CECT may improve recurrence detection in resource-constrained settings. Future studies should evaluate the survival benefits and cost-effectiveness of routine CECT surveillance in the Nepalese context.
Artificial intelligence (AI) in hematology and oncology fellowship (HOF) training: A multicenter survey of education, attitudes, and clinical use.
9001 Background: A prior national survey of U.S. HOF curricula demonstrated substantial heterogeneity and limited protected time for didactics beyond traditional lecture-based education 1 . More recently, artificial intelligence (AI), including large language models and ambient listening tools, has become increasingly integrated into trainee education and clinical practice 2-5 . We conducted a multi-center survey to assess the use of AI among HOFs. Methods: Hematology/oncology (H/O) fellows were recruited via email by program leadership to complete an anonymous survey adapted from our prior study, with added questions on AI education, attitudes, and clinical use. Responses were collected via REDCap and summarized using descriptive statistics. Results: A total of 118 H/O fellows responded from 18 of 30 invited U.S. HOF programs (60%), primarily from academic centers (94%), with a near-uniform distribution across fellowship training years. Most fellows (74%) reported using AI tools such as ChatGPT or OpenEvidence. Commonly used resources included NCCN guidelines (92%), UpToDate (86%), faculty lecture slides (70%), primary journals (65%), podcasts (58%), textbooks (29%), and social media (20%). Only 8% reported receiving AI education during HOF training. Most fellows felt AI was useful for medical education (93%) and were confident using AI tools for learning (74%). The majority anticipated increasing AI use over the next 5 years (92%) and expressed interest in AI training during fellowship (82%). Fellows most commonly used large language model–based AI tools to clarify difficult concepts (86%), summarize journal articles (83%), and learn about emerging research (75%), whereas fewer reported use for question generation (31%) or patient case simulations (29%). AI-assisted documentation was the most commonly used clinical AI application (51%). Reported barriers to AI use included (in order of highest concern): uncertainty regarding accuracy, lack of formal training, data privacy concerns, and unclear ethical or institutional guidelines. Conclusions: AI tools are widely used and perceived as useful for clinical and educational purposes by current H/O fellows, yet formal training during fellowship remains limited. These findings highlight an unmet need for structured education on effective, safe, and ethical AI use, with opportunities for multi-institutional collaboration to achieve scalable impact aligned with contemporary oncology practice.
One vs. 2 vs. ≥3 <i>TET2</i> mutations in chronic myelomonocytic leukemia: Co-mutation patterns and prognostic correlates.
6588 Background: TET2 is the most frequently mutated gene in chronic myelomonocytic leukemia (CMML) and has been associated with favorable outcome, with recent studies suggesting a more pronounced prognostic impact in the presence of ≥2 TET2 mutations ( Csizmar et al. leukemia 2025;39:2030; Kynning et al. Br J Haematol. 2025 Nov 25. doi: 10.1111/bjh.70264 ). We sought to determine if this particular observation extended to patients with ≥3 TET2 mutations ( TET2 MUT ) and also held true in the context of recently reiterated genetic risk factors. Methods: The current study was conducted under institutional review board approved minimum risk protocols allowing retrospective patient data collection and analysis. Diagnostic criteria were according to the International Consensus Classification (Arber et al. Blood 2022. 140:1200). All statistical analyses were conducted using JMP 18 software. Results: 536 CMML patients who underwent CLIA-approved NGS testing were stratified according to the number of TET2 MUT : 221 (41%) wild-type, 148 (28%) with one, 153 (29%) 2, and 14 (2%) ≥3 TET2 MUT . Co-mutation frequencies with significant differences between one vs. two TET2 MUT included ASXL1 (46% vs. 29%; p<0.01), KRAS (7% vs. 14%; p=0.02) and SETBP1 (5% vs. 0.6%; p=0.02). Phenotypic comparisons revealed preponderance of prognostically favorable traits associated with wild-type TET2 but no significant differences between one vs. two TET2 MUT . In age-adjusted univariate analysis, transplant-censored overall survival (TCOS), calculated from the time of mutation detection, was superior in patients with one (p<0.01; HR 0.7) or 2 (p<0.01; HR 0.4) but not ≥3 (p=0.4) TET2 MUT , vs. those with wild-type TET2 . TCOS was also superior with 2 vs. 1 (p=0.02; HR 0.7) but not with ≥3 vs. 1 (p=0.7) TET2 MUT ; the results were similar when TCOS was calculated from the time of diagnosis. Multivariable analysis confirmed the survival advantage of exactly two TET2 MUT vs. wild-type TET2 (p<0.01; HR 0.5), one TET2 MUT (p<0.01; HR 0.6), or ≥3 TET2 MUT (p<0.01; HR 0.4), after adjusting for age, sex, anemia, circulating blasts ≥2%, and leukocyte count ≥13×10⁹/L. The favorable impact of exactly two TET2 MUT persisted in CMML-MD and CMML-MP and remained independent of TET2 VAF, mutation type, karyotype, and other prognostically relevant mutations. This association was sustained in the BLAST (p<0.01; HR 0.5) and CPSS-mol (p=0.02; HR 0.7) models, but not in BLAST-mol model (p=0.12). Conclusions: Mechanistic explanation for this novel observation includes the possibility that TET2 mutational categories based on mutation count reflect distinct biological states rather than having a simple linear effect. The persistence of this signal despite adjustment for established molecular and genetic risk factors supports its consideration in the development of future CMML prognostic models.