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Incidence of <i>BRCA1/BRCA2</i> mutations in ovarian cancer and other solid malignancies in Caracas, Venezuela.

e23434 Background: Ovarian cancer is the second leading cause of gynecological cancer in the United States (USA), as well as the leading cause of death by gynecological cancer in that country. In Venezuela, in contrast, ovarian cancer represents the third leading cause of gynecological cancer, with one of the lowest mortality rates within the group. It is known that both BRCA1 and BRCA2 gene mutations lead to increased risk of cancer worldwide, however in Venezuela the frequency of these mutations is unknown. We sought to determine the incidence of germline and somatic BRCA 1/2 mutations in patients with several solid tumors, including ovarian cancer, at our single center institution in Caracas (Venezuela), between the years 2017 and 2024. Methods: We reviewed 230 molecular tests (40 tests from germline tests, 190 tests from somatic lines with Next Generation Sequencing) across multiple patients with different solid tumors, including ovarian cancer (excluding breast cancer). Results: We identified a total of 28 patients with mutations in BRCA genes, half of these were found on germline testing and the other half in somatic line testing (14 patients each). From the total pool of patients, 12 had a BRCA1 mutation (42.8%) and the remaining 16 on BRCA2 (57.2%). The vast majority of BRCA 1/2 mutations were found in patients with ovarian cancer (64.2%, n = 18 patients). Of the patients with ovarian cancer, 10 patients had a BRCA1 mutation and the remaining 8 had a BRCA2 mutation. Conclusions: This is the first documented report on the incidence of BRCA mutations conducted in patients with solid tumors in Venezuela. Incidence of BRCA 1/2 mutations by solid tumor type. BRCA1 mutation Number of patients (N) BRCA2 mutation Number of patients (N) Ovary N = 10 Ovary N = 8 Endometrium N = 1 Endometrium N = 2 Bladder N = 1 Bladder N = 2 Stomach N = 0 Stomach N = 2 Biliary Tree N = 0 Biliary Tree N = 2

From treatment to survivorship: The CORE randomized study of a supervised exercise intervention in early-stage breast cancer.

638 Background: Physical exercise is recommended by international guidelines to mitigate treatment-related toxicity and improve quality of life in patients with breast cancer (BC). However, adherence to physical activity recommendations remains low, and evidence from randomized studies conducted in real-world clinical settings is limited. The CORE study evaluated the impact of a structured, supervised exercise program on fatigue and health-related quality of life (HRQOL) in patients with early-stage BC. Methods: CORE is a single-center, randomized controlled trial enrolling patients with early-stage BC undergoing or recently completing curative treatment. Seventy patients were randomized 1:1 to usual care (control, n = 45) or a 3-month supervised exercise intervention (exercise, n = 45). Primary endpoints were physical fatigue (EORTC QLQ-BR45), cardiorespiratory fitness and muscle strength, and HRQOL (EORTC QLQ-C30 summary score). Secondary analyses explored changes in additional symptom and functional scales, as well as health status assessed by the EQ-5D questionnaire. Between-group differences in change from baseline to 3 months were analyzed with adjustment for multiple comparisons. Results: At 3 months, patients assigned to the exercise intervention experienced a statistically significant reduction in physical fatigue compared with usual care (mean difference −5.3; 95% CI −10.0 to −0.6; adjusted P = 0.027). HRQOL significantly improved in the exercise group (mean difference 4.8; 95% CI 2.2–7.4; adjusted P = 0.0003). In addition, within the exercise group, significant pre–post improvements were observed across several EORTC QLQ-C30 symptom and function scales, including fatigue, pain, dyspnea, nausea/vomiting, physical functioning, and role functioning, indicating a broad positive impact of the supervised strength training program on overall health status and daily functioning. Consistently, pre–post analyses in the exercise group using the EQ-5D demonstrated significant improvements in mobility, daily activities, and pain/discomfort dimensions. Conclusions: A 3-month supervised exercise program significantly reduced physical fatigue and improved HRQOL in patients with early-stage breast cancer. These findings reinforce the role of structured, supervised exercise as a key component of survivorship and supportive care, offering a scalable and effective strategy to reduce symptom burden, enhance functional capacity, and promote overall patient well-being.

Distant recurrence–free survival in invasive lobular carcinoma (ILC) with isolated tumor cells: Does pN0(i+) behave like node-negative or node-positive disease?

587 Background: ILC is a distinct breast cancer subtype with unique biology and clinical behavior compared with invasive ductal carcinoma. The prognostic significance of isolated tumor cells (ITCs; pN0(i+)) in ILC remains unclear, creating a management gap regarding whether patients with ITCs should be risk-stratified and treated similarly to node-negative (pN0) or node-positive (pN1) disease. Methods: We performed a retrospective analysis of patients with ILC treated at The University of Texas MD Anderson Cancer Center (Protocol PA20-0040). Distant recurrence-free survival (DRFS) was assessed using Kaplan-Meier methods and compared using log-rank testing. Univariate and multivariable Cox proportional hazards models evaluated associations between clinicopathologic and treatment variables and DRFS. The multivariable model included age, pathologic nodal stage, grade, HER2 status, histologic subtype (classical vs non-classical), and receipt of endocrine therapy, chemotherapy, radiation therapy, and definitive surgery. Results: The cohort included 4,217 patients (mean age 56.8 years). Most tumors were classical ILC (89.1%). ITCs were present in 169 patients; comparator groups included pN0 (n=1,799) and pN1 (n=1,040). In univariate analysis, there was no evidence that pN0(i+) were associated with worse DRFS versus pN0 (ITC negative) (HR 0.71, 95% CI 0.45-1.13; p=0.135), whereas pN1 was associated with inferior DRFS versus pN0 (HR 1.85, 95% CI 1.62-2.10; p&lt;0.001). In multivariable analysis, there remained no evidence that pN0(i+) were associated with inferior DRFS versus pN0 (HR 0.661, 95% CI 0.404-1.081; p=0.099), while pN1 was independently associated with worse DRFS versus pN0 (HR 1.922, 95% CI 1.589-2.326; p&lt;0.0001). Conclusions: In this large ILC cohort, pN0(i+) (ITCs) did not confer inferior DRFS compared with pN0, and outcomes were clearly distinct from pN1 disease. These findings support prospective validation and may inform nodal-status-driven risk stratification and treatment de-escalation strategies for pN0(i+) patients with ILC. Key DRFS comparisons (reference = pN0). Comparison Univariate HR (95% CI) Univariate p-value Multivariable HR (95% CI) Multivariable p-value pN0(i+) vs pN0 0.71 (0.45-1.13) 0.135 0.661 (0.404-1.081) 0.099 pN1 vs pN0 1.85 (1.62-2.10) &lt;0.001 1.922 (1.589-2.326) &lt;0.0001

Safety of glucagon-like peptide-1 receptor agonists in patients receiving chimeric antigen receptor T cell or bispecific T cell engager therapy.

e24016 Background: Chimeric antigen receptor T-cell (CAR-T) and bispecific T-cell engager (BiTE) therapies are associated with significant toxicities, including cytokine release syndrome (CRS), infections, and cardiometabolic complications. GLP-1 receptor agonists (GLP-1RAs) have immunometabolic effects that may theoretically influence inflammatory toxicities during T-cell–redirecting therapies; however, their safety in patients undergoing CAR-T or BiTE therapy remains poorly defined. Methods: We conducted a retrospective, multicenter cohort study using the TriNetX database, including adults (≥18 years) with hematologic malignancies receiving FDA-approved CAR-T/BiTE therapy. Patients were stratified by GLP-1RA exposure (between 1 month and 1 year of CAR-T/BiTE therapy) and compared with GLP-1RA-naïve controls. Cohorts were propensity score matched 1:1 for age, sex, malignancy type, and baseline comorbidities (heart failure, diabetes, prior myocardial infarction). Primary outcome was 1-year all-cause mortality as a global safety endpoint, and secondary outcomes were CRS, tocilizumab use, and C-reactive protein (CRP) levels. Cohort comparisons were performed using built-in TriNetX statistical methods, with regression-based estimates reported as odds ratios (ORs) and time-to-event analyses using Cox proportional hazards models. Results: Among patients receiving CAR-T/BiTE therapy, 141 with prior GLP-1RA exposure were identified and propensity score–matched to GLP-1RA–naïve controls. No significant difference in mortality was observed between groups (OR 1.29, 95% CI 0.76–2.20). Similarly, GLP-1RA exposure was not associated with differences in CRP levels (p = 0.26), tocilizumab utilization (OR 0.79, 95% CI 0.47–1.35), or incidence of CRS (OR 1.49, 95% CI 0.68–3.26). Conclusions: GLP-1RA use was not associated with increased toxicity, inflammatory complications, or mortality in patients undergoing CAR-T or BiTE therapy, supporting the short-term clinical safety of GLP-1RA exposure in this high-risk population.

Immune checkpoint inhibitors plus chemotherapy versus chemotherapy alone as first-line treatment for unresectable or metastatic esophageal carcinoma: A systematic review and meta-analysis of randomized trials.

e16083 Background: Immune checkpoint inhibitors (ICIs) combined with chemotherapy are standard first-line therapy for advanced esophageal squamous cell carcinoma (ESCC); however, their benefit in esophageal adenocarcinoma (EAC) and across programmed death-ligand 1 (PD-L1) subgroups remains uncertain. Given substantial histologic heterogeneity, we performed a systematic review and meta-analysis to critically assess the efficacy and safety of first-line ICI-chemotherapy in advanced esophageal carcinoma. Methods: PubMed, Embase, Cochrane Central, and major oncology conference proceedings were searched through April 2024 for phase II/III randomized trials comparing anti–PD-1/PD-L1–based ICI plus platinum/fluoropyrimidine chemotherapy versus chemotherapy alone in treatment-naïve patients with unresectable or metastatic esophageal carcinoma. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) and grade ≥3 treatment-related adverse events (TRAEs). Random-effects models were used to estimate pooled hazard ratios (HRs) and odds ratios (ORs). Prespecified subgroup and interaction analyses were conducted by histology, PD-L1 combined positive score (CPS), and liver metastases. Risk of bias was assessed using the Cochrane RoB 2 tool. Results: Seven trials comprising 4,812 patients were included. ICI-chemotherapy significantly improved OS (HR 0.68, 95% CI 0.63–0.74) and PFS (HR 0.62, 95% CI 0.57–0.67) versus chemotherapy alone. OS benefit was robust in ESCC (HR 0.68, 95% CI 0.62–0.74) but not statistically significant in EAC (HR 0.74, 95% CI 0.54–1.02). OS benefit was observed in PD-L1 CPS ≥10 and CPS &lt; 10 subgroups without significant interaction (p = 0.09). Patients with liver metastases derived significantly less OS benefit (p-interaction = 0.04). ORR favored ICI-chemotherapy (OR 1.82, 95% CI 1.52–2.17), with higher grade ≥3 TRAEs (OR 1.32, 95% CI 1.12–1.56). Most trials were ESCC-dominant. Conclusions: First-line ICI-chemotherapy confers a meaningful survival advantage in advanced esophageal carcinoma, driven primarily by ESCC. Evidence in EAC remains inconclusive and underpowered. Apparent benefit across PD-L1 CPS strata and reduced efficacy in liver metastases emphasize the need for histology-specific and biomarker-refined strategies.

Impact of immunonutrition in patients undergoing hepatectomies for liver tumors: A randomized controlled phase II trial.

TPS4259 Background: Recent studies have demonstrated that immunonutrition has the potential to improve the host immune state, reduce infectious complications, and shorten the length of hospital stay after major abdominal surgeries. Controversy still persists regarding whether or not perioperative immunonutrition could offer substantial benefits to patients undergoing hepatectomy as compared with standard nutrition. Several biomarker-based indices reflecting the immune as well as nutritional status, have been investigated, to predict postoperative morbidity following major hepatectomies. One such index, validated in a meta-analysis is the prognostic nutritional index (PNI). Prognostic Nutritional Index (PNI) = [(10 × serum albumin (g/dL)) + (0.005 × total lymphocyte count)], with higher PNI correlating with improved survival outcomes . Based on this we aim to conduct a randomized controlled trial to evaluate the improvement of PNI, by immunonutritional intervention in patient undergoing major hepatectomies. Methods: Study Design: Open labelled, Phase II randomized controlled trial. Eligibility criteria: Inclusion: (1) Patients with liver tumors planned for major hepatectomies (defined as resection of &gt;/= 3 liver segments); (2) Age above 18 years; (3) ASA class I-III. Exclusion: (1) Preoperative severe renal failure (estimated glomerular filtration rate &lt; 30 ml/min); (2) History of hypersensitivity to arginine, omega-3 fatty acids, or nucleotide; (3) Inability to take oral nutrition; (4) Pregnancy; (5) Mental condition rendering the subject unable to understand the nature, endpoints and consequences of the trial. Interventions: Randomization will be carried out centrally at the Clinical Research Secretariat, Tata Memorial Hospital. The trial statistician will generate a permuted-block randomization sequence using variable sized blocks of 2, or 4, without any stratification factors. Participants will be randomly assigned in 1:1 to receive either the intervention or control. Details of Intervention: In addition to their usual intake, patients in the intervention arm will be prescribed for each of the 7 consecutive days preceding surgery 6-9 scoops Immunomax powder (120-180g per day), based on weight. At recruitment, blood samples will be taken for inflammatory and immune status markers. These measurements will be repeated on the day prior to surgery (D-1) and on POD 1, 3, 5 and 7. An additional Creactive protein (CRP) measurement will be taken on POD30. PNI will be calculated before the intervention and on the day prior to surgery. Primary Endpoints: Mean difference in PNI points between intervention and control group. Secondary Endpoints: (1) Incidence of postoperative complication; (2) Incidence of post-hepatectomies liver failure (PHLF); (3) Length of ICU stay; (4) Length of hospital stay; (5) Incidence of 90 days mortality. 100 patients will be enrolled over 2 years. Clinical trial information: CTRI/2025/06/088908.

Efficacy and safety of iberdomide, daratumumab, bortezomib, and dexamethasone in patients with newly diagnosed multiple myeloma.

7514 Background: Iberdomide (Iber) is a CELMoD that binds with greater specificity &amp; affinity to the cereblon protein of the E3 ligase complex than a traditional IMiD. Both transplant-eligible (TE) &amp; ineligible (TIE) patients (pts) with newly diagnosed multiple myeloma (NDMM) are currently treated with quadruplet induction, consisting of an anti-CD38 monoclonal antibody, a proteasome inhibitor, an IMiD &amp; dexamethasone (dex). We conducted a clinical trial (NCT05392946, IDEAL) to examine the efficacy of a novel finite-duration approach, using Iber, daratumumab, bortezomib &amp; dex (Iber-DVd) quadruplet induction followed by Iber monotherapy maintenance. Methods: Both TE and TIE pts with NDMM were enrolled in this Phase 1 (3+3 design)/Phase 2 (single stage) trial. The primary goal was to assess the ≥complete response (CR) rate — utilizing the more sensitive serum MASS-FIX assay in lieu of serum immunofixation — during induction. Treatment involved twelve 28-day cycles of induction with Iber, given PO at the recommended phase 2 dose (RP2D), days 1-21, daratumumab 1800mg SQ, weekly for 2 cycles, every other week during Cycles 3-6, &amp; every 4 weeks thereafter, bortezomib 1.3 mg/m 2 SQ, weekly &amp; dex 40 mg, weekly, followed by Iber monotherapy (24 cycles). Growth factor was not allowed during the dose-limiting toxicity (DLT) assessment period (Cycle 1). Results: Among 47 pts enrolled, 9 pts were in Phase 1 portion which assessed the maximum tolerated dose (MTD), with Iber starting at 1 mg/day dose, days 1-21 [Dose Level (DL) 1]. DLT (all grade 4 neutropenia) was noted in 3 pts, 2 at DL 1 &amp; 1 at DL -1. This analysis includes 44 pts who received Iber at the RP2D (0.75 mg/day, days 1-21), including 6 pts from the Dose Confirmation Cohort (Phase 1, DL -1), dosed at MTD, &amp; 38 pts in the Dose Expansion Cohort. The median age at registration was 65 years (range 36-86 years), &amp; 23 pts (52.3%) were deemed high-risk. At data cut-off, pts had received a median of 15 cycles (range 3-36) of therapy. Overall response rate was 100%; ≥CR rate, 36.4% (95% CI: 22.4, 52.2) during induction &amp; 52.3% (95% CI: 36.7, 67.5), overall, including the maintenance phase. The marrow flow-based (10 -5 ) MRD negative rate was 29.5% during induction &amp; 47.7% overall. At a median follow-up (FU) 18.3 mos, 2 pts have died (one during FU due to progressive disease &amp; the other on-treatment due to COVID-19). 12- (&amp; 18-) month progression-free survival &amp; overall survival rates were 91% (88%) &amp; 97% (94%), respectively. Most common toxicities at RP2D were lymphopenia, neutropenia (leading 27% of pts to require pegfilgrastim support), rash, peripheral neuropathy, diarrhea, &amp; infections. Cases of high-grade fatigue were low (&lt;5%). Updated data will be presented at the meeting. Conclusions: Iber-DVd is an active and safe regimen for both TE and TIE pts with NDMM, leading to high response rates which improved over time, with nearly one-half of the pts achieving MRD negative state. Clinical trial information: NCT05392946 .

Narcolepsy and skin cancer risk: Inverse comorbidity and the protective role of orexin deficiency.

e21575 Background: Narcolepsy is a disorder characterized by daytime sleepiness, potential cataplexy, and hallucinations. The condition is subdivided into narcolepsy type 1 (NT1), involving orexin (or hypocretin) deficiency; and narcolepsy type 2 (NT2), which does not. Malignancy risk has had limited investigation with narcolepsy; limited to retrospective analysis of a Taiwanese database that found an increased cancer risk in 2833 narcoleptic patients with increased incidence in females. Orexin is a neuropeptide with an emerging role in cancer development, with pro-apoptotic evidence in colon, pancreatic, prostate, and neuroblastomas, but anti-apoptotic evidence in gastric cancers. Hence, we aimed to conduct a large retrospective cohort study of narcolepsy and melanoma and non-melanoma skin cancer (NMSC) risk, with the first subtype analysis of NT1 and NT2. Methods: The TriNetX US database was utilized, providing real-world, de-identified data of 124 million patients. Exposed patients were defined as having at least 2 instances of the ICD-10 code, G47.41, for narcolepsy. The control cohort was defined by having no history of narcolepsy and at least 2 general outpatient annual physical examinations (Z00.0). For subgroup analysis, NT1 and NT2 cohorts were defined using at least two instances of ICD-10 coding G47.411 or G47.419. Patients were propensity score matched 1:1 by age at index, sex, Hispanic ethnicity, and Black and White race. Results: 43,463 patients with narcolepsy were included to matched unexposed. Narcoleptic patients had a significant decrease in risk of basal cell carcinoma (BCC) (RR 0.615, p&lt;0.0001) and squamous cell carcinoma (SCC) (RR 0.686, p&lt;0.0001). In subgroup analysis by sex, females with narcolepsy had a significantly decreased risk of BCC (RR 0.656, p=0.0001) and SCC (RR 0.532, p&lt;0.0001) compared to males. Additionally, patients with NT1 had significantly decreased risk of melanoma (RR 0.575, p=0.0200) and BCC (RR 0.752, p=0.0415) compared to patients with NT2. Conclusions: In prior studies of narcolepsy, it was suggested that patients have a higher risk of malignancy; however, our findings support potential for inverse comorbidity in the context of cutaneous malignancies. Our findings suggest that patients with narcolepsy may have a decreased risk of NMSC, with decreased risk in females compared to males. Additionally, NT1, orexin deficient patients, may have significantly decreased risk of melanoma and NMSC compared to NT2 patients.

Real-world experiences with a multi-cancer detection (MCD) blood test.

10565 Background: Multi-cancer detection (MCD) blood tests hold promise to screen for multiple cancers simultaneously. MCD tests have been assessed in case-control and prospective studies but have not yet been shown to improve cancer outcomes. Mass General Brigham (MGB) offers a commercially available, non-FDA-approved methylation-based MCD test (Galleri; GRAIL) through our Early Detection &amp; Diagnostics Program. Here, we report our initial experience. Methods: In this retrospective, observational study, data were collected from all patients (pts) who underwent MCD testing or were evaluated for a prior positive MCD test at our clinic between May 2023 and December 2024. Pts obtained the test through: 1) self-payment after shared decision making, or 2) an early access demonstration project with GRAIL, Point32Health (insurance company), and MGB whereby pts ≥50y with specific insurance products and an MGB primary care physician were invited to receive a cost-free test if they met ≥1 of 4 criteria: personal history of cancer, 1st-degree family history of cancer, elevated BMI, or any smoking history in the past 10 years. All pts tested at MGB underwent pre-test consultation with a medical oncologist or nurse practitioner to review the benefits and limitations of testing. Result management was coordinated by our team. Longitudinal outcomes were abstracted from electronic health records. Results: 742 pts had MCD testing (125 [17%] self-pay, 617 [83%] demonstration project). Median (med) age was 59 (IQR 55-63); most were White (92%) and up to date on USPSTF-recommended cancer screening (82%). Med follow up (FU) was 469 days (IQR 462-478); 580 (78%) had &gt; 12 months FU. Four pts received a “cancer signal detected” result (+MCD): 2/742 tested at MGB (0.3%) and 2 who presented to workup +MCD tested elsewhere; 2 were true positives (TP), 2 false positives. In total, 16 pts (2.2%) were diagnosed (dx) with cancer during FU; 2/16 (13%) after +MCD, and 14/16 after negative MCD, with med time from MCD to diagnosis 199 days (IQR 92-464). The two TP tests corresponded to stage I breast cancer and stage III follicular lymphoma. The most common cancers dx were prostate (n = 5, with two stage III-IV dx at 128 and 142 days) and breast (n = 4, all mammogram-detected stage I). Other advanced cancers included stage III cholangiocarcinoma and stage IV adenocarcinoma unknown primary (dx at 515 and 475 days, respectively). Conclusions: In this real-world cohort, MCD test positivity was rare, and multiple cancers were dx within 18 months of a negative MCD, including some advanced cases. In particular, prostate cancer was dx in multiple pts after negative MCD, consistent with prior reports of limited MCD sensitivity for prostate cancer. Our cohort may be biased by the requirement to either self-pay or carry a specific insurance product. Larger studies with longer FU are needed to better define the added utility of MCD tests to standard cancer screening.

Baseline inflammatory indexes and prognosis for progression-free survival in first-line pembrolizumab plus chemotherapy for PD-L1-positive advanced triple-negative breast cancer: A Polish multicenter cohort study.

e13108 Background: Advanced cancer is a systemic disease with inflammation recognized as one of its key hallmarks. Ratios such as Systemic Immune-Inflammation Index (SII), Systemic Inflammation Response Index (SIRI), Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR) and Lymphocyte-to-Monocyte Ratio (LMR) reflect systemic inflammatory status and are considered valuable prognostic biomarkers in patients treated with immune checkpoint inhibitors. However, data regarding their relevance in PD-L1-positive metastatic triple-negative breast cancer (mTNBC) receiving first-line pembrolizumab plus chemotherapy remain scarce. In this study, we evaluated whether baseline inflammatory indexes predict progression-free survival (PFS) in a multicenter Polish cohort treated with chemoimmunotherapy. Methods: This retrospective study included 89 women who initiated chemotherapy and pembrolizumab from September 2022 to February 2025 in 13 oncology centers in Poland. Complete blood count was assessed before treatment initiation. Systemic inflammation indexes were calculated as SII = (platelet count × neutrophil count) / lymphocyte count, SIRI = (neutrophil count × monocyte count) / lymphocyte count, NLR = neutrophil count / lymphocyte count, PLR = platelet count / lymphocyte count, LMR = lymphocyte count / monocyte count. Median PFS was estimated and associations between baseline inflammatory indexes and PFS were assessed using multivariate Cox regression models (α = 0.05). Results: The median follow-up was 10.1 months (IQR 5.5–14.8) and mPFS was 9.3 months (95% CI: 6.6–14.7). OS data were immature (n = 15 deaths). Due to multicollinearity (VIF &gt; 10), SII was excluded from the final multivariable Cox model. The proportional hazards assumption was met for all variables, and diagnostic plots confirmed the absence of influential observations and preserved model linearity. The final multivariable model included SIRI, NLR, PLR, and LMR. None of the inflammatory indices demonstrated a statistically significant association with PFS. Hazard ratios (HRs) with 95% confidence intervals (CI) were as follows: SIRI HR 1.14 (95% CI 0.84–1.53; p = 0.41), NLR HR 1.04 (95% CI 0.84–1.30; p = 0.72), PLR HR 1.00 (95% CI 0.99–1.00; p = 0.42) and LMR HR 0.85 (95% CI 0.63–1.14; p = 0.27). Global model tests were not statistically significant (likelihood ratio p = 0.20; Wald p = 0.20; score p = 0.20). The concordance index was 0.59, indicating limited discriminative performance. Conclusions: In this real-world cohort, inflammatory indexes did not serve as prognostic factors for PFS in patients with PDL1-postive mTNBC treated with chemoimmunotherapy. These findings highlight the need for alternative biomarkers to optimize treatment.

Patient-reported performance status as a predictive tool for mortality and supportive care needs in patients with advanced cancer.

1569 Background: Performance status is a key prognostic factor among patients with advanced cancer and can inform the need for supportive care services. However, assessment and documentation of performance status is inconsistently integrated into standard oncology care. Patient-reported performance status (PRPS) is a surrogate for clinician-assessed performance status and has the potential to address this challenge. We piloted a decision support tool in our electronic health record (EHR) that uses PRPS to prompt clinician assessment of performance status and suggest referrals to supportive care services. Methods: We identified patients with advanced cancer using a pre-built and validated registry driven by ICD codes in our EHR (EPIC). For patients with advanced cancer seen at one of our clinics, a multiple-choice question with options derived from the Eastern Cooperative Oncology Group (ECOG) scale in patient-friendly language was added to the pre-visit questionnaire sent electronically prior to oncology visits. For patients with a poor PRPS (2 or greater), a clinical decision support tool alerted providers of the patient’s self-reported performance status, encouraged input of the clinician’s ECOG assessment, and suggested referral orders to supportive care services such as palliative care, nutrition, and social work. We assessed the relationship between PRPS and ECOG with mortality using logistic regression and by calculating median time to death stratified by patients’ highest (poorest) score. Results: Between 3/11/24 and 3/11/25, 3,376 PRPS surveys were completed by 1,343 oncology patients. Seventeen percent of patients reported poor PRPS (≥2). Worsening PRPS was strongly associated with mortality (3% for PRPS 0 vs. 44% for PRPS 4) and with shorter median time-to-death (163 days for PRPS 0 vs. 19 days for PRPS 4). PRPS correlated with clinician-assessed ECOG (ρ=0.3, p&lt;0.001) and predicted mortality (ρ=0.8) comparably with ECOG (ρ=0.7). By contrast, ECOG documentation by clinicians was incomplete in 39% of patients. Conclusions: Results suggest feasibility of a PRPS-driven decision support tool to flag patients with advanced cancer and declining function at greatest risk of mortality. PRPS can help allocate limited supportive care resources and prompt advance care planning discussions for patients with greatest need.

Inpatient burden and outcomes across gastrointestinal cancer subtypes among younger adults in the United States, 2018–2022.

11077 Background: Early-onset gastrointestinal (GI) cancers are increasingly recognized, yet national data describing inpatient burden and outcomes across GI cancer subtypes in younger adults remain limited. Methods: A serial cross-sectional analysis was performed using the 2018–2022 Healthcare Cost and Utilization Project National Inpatient Sample. Adult hospitalizations among younger adults (age 18–49 years) with a principal diagnosis of GI malignancy were identified and categorized by cancer subtype. Outcomes included in-hospital mortality (primary), length of stay (LOS), and hospitalization cost estimated using cost-to-charge ratios. National estimates accounted for survey weighting, clustering, and stratification. Survey-weighted multivariable logistic regression evaluated associations between cancer subtype and in-hospital mortality, adjusting for age, sex, race/ethnicity, payer, neighborhood income quartile, elective admission, APR-DRG severity, hospital teaching status, geographic region, and calendar year. Sensitivity analyses were performed restricting the cohort to age &lt; 45 years. Results: Across 2018–2022, principal GI cancer hospitalizations among younger adults were dominated by colorectal cancer, followed by stomach, pancreatic, liver or intrahepatic biliary, and esophageal cancers. In-hospital mortality varied by cancer subtype and year, with higher crude mortality observed for pancreatic, stomach, esophageal, and liver or intrahepatic biliary cancers compared with colorectal cancer. Resource utilization increased markedly during 2020 across subtypes, with corresponding increases in LOS and hospitalization costs. In adjusted analyses using colorectal cancer as the reference, odds of in-hospital mortality were higher for stomach (adjusted odds ratio [aOR] 3.01, 95% CI 1.78–5.10), esophageal (aOR 2.12, 95% CI 1.03–4.37), and liver or intrahepatic biliary cancers (aOR 2.56, 95% CI 1.36–4.79). Pancreatic cancer demonstrated a borderline increase in mortality (aOR 1.79, 95% CI 0.96–3.36). Higher APR-DRG severity was strongly associated with mortality (aOR 5.20, 95% CI 3.50–7.72). Sensitivity analyses demonstrated similar subtype ordering and mortality patterns. Conclusions: Among younger adults hospitalized with GI malignancies, inpatient mortality and resource utilization varied substantially by cancer subtype. Colorectal cancer accounted for the largest share of hospitalizations, while stomach, esophageal, and liver or intrahepatic biliary cancers were associated with higher adjusted inpatient mortality. These nationally representative findings provide benchmarking data on inpatient outcomes across early-onset GI cancer subtypes.

Validation of melanoma immune profile (MIP) to predict RFS in stage II-III melanoma on adjuvant interferon trial (E1697).

e21596 Background: Development of prognostic biomarkers are urgently needed for patients with stage II-III melanoma to stratify for clinical trials. We performed a blinded retrospective prospective validation study of MIP, a previously defined immunogenomic signature using specimens from the E1697 study of adjuvant interferon conducted between 2000 and 2010. Methods: RNA was extracted from 20-micron sections using PureLink FFPE kit and quantified using the nCounter Platform (NanoString) from 169 patients. 7 specimens were excluded because they were stage I tumors, 3 for desmoplastic pathology, and 2 due to lack of clinical follow up. RNA was obtained successfully from all specimens and MIP score was calculated according to published methods. To test signature performance, Kaplan–Meier (KM) curves were plotted with log-rank test, and univariable and multivariable cox proportional hazards models adjusted with significant clinical predictors of lymph node status and ulceration were fitted. Results: Among 157 patients from the E1697 study, 40.8% were female, median age was 52.9 years and 21.7% stage III. with median RFS (mRFS) of 49.2 months. 139 were classifies as low risk and 19 as high risk. KM analysis showed that unfavorable MIP correlates with shortened RFS (p = 0.002, with mRFS 1.85 years vs undefined). Univariable cox analysis also correlated with RFS (p = 0.002, HR = 2.69, 95% Cl: 1.4-5.1). In this cohort lymph node status (p &lt; 0.0001) and ulceration (p = 0.0166) correlated with RFS whereas Breslow depth did not (p = 0.236). MIP remained associated with a prolonged mRFS when lymph node status and ulceration were taken into account in a multivariable model. (p = 0.012, HR = 2.35, 95% Cl: 1.2-4.6). Conclusions: MIP is the first melanoma biomarker to be validated on national trial data in a blinded fashion. It should be further validated in prospective studies for use as a stratification metric in clinical trials.

Bacillus Calmette-Guérin (BCG) and Beyond: Is Systemic Immunotherapy for BCG-Naïve Non–Muscle-Invasive Bladder Cancer Progress or Overreach?

Tarlatamab in small cell lung cancer with brain metastases: A real-world experience.

8108 Background: Tarlatamab, a DLL3-directed bispecific T-cell engager, has demonstrated survival benefit in previously treated small cell lung cancer (SCLC) in pivotal clinical trials. However, real-world evidence remains limited, particularly in ethnically diverse populations and in patients with a high burden of central nervous system (CNS) disease who are often underrepresented in clinical trials. We evaluated the safety, radiographic response, and treatment durability of tarlatamab in a real-world cohort treated at a single academic center. Methods: We retrospectively reviewed patients with extensive-stage SCLC treated with tarlatamab at Sylvester Comprehensive Cancer Center between January 2024 and October 31, 2025. Demographic, clinical, radiographic, and toxicity data were abstracted from medical records. Radiographic response was assessed per RECIST criteria, with best overall and 6-month responses recorded. Objective Response Rate (ORR) and Disease Control Rate (DCR) were calculated. Progression-free survival (PFS) and Overall Survival (OS) were estimated using Kaplan–Meier methods with multivariable analyses performed using Cox regression. Results: Among 23 patients (median age 72 years), male sex, Hispanic ethnicity, and brain metastases were each present in 61% of the cohort at tarlatamab initiation. 43% had received ≥2 prior lines of therapy. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANs) occurred predominantly during cycle 1 and were limited to grade 1 or 2 events, with no grade ≥ 3 toxicities observed. Median time on treatment was 92 days, with a median of 4 cycles. Three patients required treatment discontinuation due to toxicities. Radiographic response was evaluable in 18 patients; five were not evaluable due to early death after cycle 1 day 1 (n=2), loss to follow-up (n=2), and transition to hospice after first cycle (n=1). In those 18 patients, best overall response included partial response in 5 patients (27.7%) and stable disease in 3 patients (16.7%), yielding an ORR of 27.7 % and a DCR of 44.4%. Median PFS was 139 days, and median OS was 323 days (95 % CI, 31 to 614). No variables were independently associated with outcomes on multivariable Cox proportional regression analysis. Conclusions: In a predominantly Hispanic, heavily pretreated real-world SCLC population with a high prevalence of brain metastases, tarlatamab demonstrated feasible administration, manageable immune-mediated toxicity, and clinically meaningful antitumor activity. These findings support the effectiveness of tarlatamab beyond clinical trial populations and highlight the importance of real-world evidence in informing care for underrepresented patients. Best Overall Response N (%) Complete Response 0 (0) Partial Response 5 (27.7) Stable Disease 3 (16.7) Progression of Disease 10 (55.5) ORR 5 (27.7) DCR 8 (44.4)

Investigation of the role of IFITM3 and the PI3K/Akt axis in the acute myeloid leukemia tumor microenvironment.

6522 Background: Interferon-induced transmembrane protein 3 (IFITM3) is overexpressed in acute myeloid leukemia (AML) and is associated with poor prognosis. Previous studies have implicated IFITM3 in oncogenic processes and immune modulation; however, the mechanisms through which IFITM3 contributes to leukemogenesis and shapes the immune microenvironment in AML remain unclear. Methods: The clinical and immunological significance of IFITM3 in AML was analyzed using scRNA-seq and bulk transcriptomic datasets. IFITM3-knockdown Kasumi-1 and ME-1 cells were established to evaluate their impact on cell proliferation and cycle progression via MTT and flow cytometry. A Transwell co-culture system was employed to assess AML-induced M0 macrophage polarization, quantified by surface markers (CD80/CD163) and cytokine profiling (ELISA/qRT-PCR). Mechanistically, GSEA were performed to identify downstream pathways, followed by Western blot validation. The functional role of the PI3K/Akt axis was further verified using the specific inhibitor LY294002. Results: Our results revealed for the first time that IFITM3high AML cell lines polarize M0 macrophages into an M2-like phenotype. Knockdown of IFITM3 led to a significant reduction of the M2 marker CD163, accompanied by an increase of the M1 marker CD80. In parallel, IFITM3-deficient AML cells exhibited decreased M2-associated gene expression and diminished secretion of TGF-β and IL-10, together with lower viability and G0/G1 cell-cycle arrest. Molecular mechanism studies revealed that loss of IFITM3 markedly reduced Akt and p-Akt protein levels. Crucially, pharmacological inhibition of the PI3K/Akt pathway using a PI3K inhibitor rescued the IFITM3-mediated effects, suppressing AML cell proliferation and M2 macrophage polarization. Clinically, we extended the adverse prognostic effect of IFITM3 to AML patients with intermediate molecular risk. Conclusions: These findings provide comprehensive evidence that IFITM3 promotes leukemic cell proliferation and contributes to a tumor-supportive AML microenvironment by driving M2 macrophage polarization via the PI3K/Akt signaling axis. These results highlight IFITM3 as a promising therapeutic target and suggest that PI3K inhibitors may offer a precision medicine approach for AML patients with elevated IFITM3 expression.

Analysis of <i>BRCA1/2</i> pathogenic variants, homologous recombination deficiency, and MYC amplification in the outcomes of advanced ovarian cancer.

e17585 Background: The association between BRCA1/2 pathogenic variants (PVs) and ovarian cancer is well established as these mutations give rise to homologous recombination deficiency (HRD) leading to DNA damage. However, the roles of BRCA1/2 PVs, HRD, and MYC amplifications in survival outcomes of patients with advanced epithelial ovarian carcinoma remain incompletely understood. Methods: Our study examines a large cohort of patients (n = 1060) with advanced epithelial ovarian cancers with genomic profiling performed using next-generation sequencing (StrataNGS). Cox regression modeling was used to examine the association between BRCA1/2 PVs, HRD, and MYC amplifications with overall survival (OS), adjusting for covariates, including age, race/ethnicity, performance status, Charlson Comorbidity Index, and other genomic alterations. Results: Our study cohort consisted of 924 patients with high grade serous ovarian cancer (HGSOC), among which 10.7% had BRCA1 PV and 5.6% had BRCA2 PV. BRCA1 patients had a lower mean age of 56 compared to those with BRCA2 and BRCA1/2 wild type (WT) who had mean ages 64 and 65, respectively (p-value &lt;1e-05). Asian patients compared with White patients had better OS (hazard ratio [HR] = 0.38, [95% confidence interval [CI], 0.17-0.84]). Other racial and ethnic groups did not show significantly different OS compared with White patients. Approximately 87.6% of patients with BRCA1 PV, 76% of patients with BRCA2 PV, and 28.9% of patients with BRCA1/2 WT were exposed to Poly(ADP-ribose) polymerase inhibitor (PARPi). By Kaplan-Meier plots, BRCA1 PV versus WT (42.7 versus 31.6 months, log-rank p = 0.030) and BRCA2 PV versus WT (60.6 versus 31.6 months, log-rank p = 0.019) were associated with superior survival, with HR of 0.63, [95% CI, 0.48-0.83] for combined BRCA1 and BRCA2 PVs. All HRD-positive tumors compared to HRD-negative tumors had superior OS (HR = 0.73, [95% CI, 0.56-0.95]). MYC amplification co-occurred in 12.4% of patients with BRCA1 and 0% of BRCA2 . Within the BRCA1 sub-cohort, MYC amplification was associated with worse OS (HR = 2.80, [95% CI, 1.06-7.38]). Conclusions: Our data confirmed improved OS associated with BRCA1/2 PVs and HRD, likely due to both the biological effect of the genomic alterations and PARPi treatment. Our data suggested that MYC amplification, which only occurred in the BRCA1 sub-cohort, was associated with worse OS. Our findings may aid in prognostic stratification in clinical practice and provide insight for further investigation into the oncogenesis of ovarian carcinoma.

Ablation success and long-term recurrence with low-dose versus high-dose radioiodine for remnant thyroid ablation in differentiated thyroid carcinoma: A systematic review and meta-analysis of randomized controlled trials.

e18119 Background: Differentiated thyroid carcinoma (DTC) is the most common endocrine malignancy. It is typically managed with thyroidectomy followed by remnant ablation using radio-iodine (RAI) therapy which reduces recurrence risk and facilitates follow up. Although high-dose RAI (100-150 mCi) has been the standard treatment, low-dose regimens (30-50 mCi) may reduce radiation exposure and toxicity, but their comparative efficacy in achieving ablation success and preventing recurrence remains uncertain. We performed a systematic review and meta-analysis of randomized controlled trials comparing low-dose versus high-dose radio-iodine for remnant thyroid ablation. Methods: A comprehensive search of PubMed, Cochrane library,and clinicaltrials.gov was conducted from inception until September, 2025.Data on ablation outcomes and long-term recurrence rate was extracted. Data was analyzed on R studio version 4.1.1, forest plots were generated using random effect model, and heterogeneity was assessed using I² statistics. Results: Sixteen randomized control trials including 4,047 patients (n=2,098 low dose; n=1,949 high dose) were analyzed. Initial ablation success was reported in 14 trials (n=3,385) and indicated that high-dose radio-iodine significantly improved initial ablation success compared to low-dose (RR: 0.93, 95% CI 0.89–0.98; P = 0.0083; I² = 40%). Long-term recurrence was reported in 8 studies including 2,983 participants. There was no statistically significant difference between low- and high-dose radioiodine (RR 0.94, 95% CI 0.63–1.42; P = 0.78), with high consistency across trials (I² = 0%). Conclusions: This meta-analysis demonstrates that high-dose radio-iodine statistically improves initial ablation success compared to low-dose in patients with differentiated thyroid carcinoma; however, long-term recurrence rates are similar between doses. These findings highlight that careful patient selection and further studies with standardized follow up are warranted to optimize dosing strategy.

Spatial analysis and deep learning integration to enhance tumour classification in total-body PET/CT imaging: A preliminary study.

e17001 Background: Accurate identification of metastases with TNM classification on 68 Ga-PSMA-11 PET/CT scans is critical for prostate cancer staging and monitoring including disease progression, however this still present challenges for conventional AI methods with computer vision. This study aims to enhance diagnostic accuracy by proposing a novel quantitative spatial analysis method using machine learning that can classify lesions in TNM staging. Integrating this method with automated machine learning based lesion segmentation improves efficiency of clinical workflows of 68 Ga-PSMA-11 PET/CT scans. Methods: 297 total-body 68 Ga-PSMA-11 PET/CT scans containing 3,771 lesions were selected for training. Lesions were segmented using a deep learning model developed in house, and major organs were automatically delineated on CT images using open-source organ segmentation tool TotalSegmentator. Spatial features were then computed to quantify each lesion’s anatomical relationships to organs (e.g., distances to organ surfaces and centroid, 3D bounding boxes coordinates, overlaps, etc). These features, along with imaging data, were used to train two complementary machine-learning classifiers—a convolutional neural network (CNN) and a graph neural network (GNN)—to predict each lesion’s category. Results: both the CNN and GNN classifiers achieved 95.7% overall accuracy in lesion classification on our with total-body PSMA PET/CT scans containing 92 lesions. The inclusion of spatial features noticeably improved the models’ ability to discriminate between different TNM staging. The model achieved class-specific accuracy for regional lymph nodes (N) and distinct metastasis (M) with respectively. Conclusions: In this preliminary study, we have developed a novel TNM lesion-level classification method that focus on quantitative spatial features on total-body 68 Ga-PSMA-11 PET/CT, and achieved promising results with overall classification accuracy 95.7%. These results indicate that explicit lesion-to-organ spatial relationships can help to more reliably distinguish regional lymph node lesions from distant metastases in the presented model. The proposed method is a step towards clinically utility when combined with the automated lesion segmentation model, which can generate structured staging output. This novel AI-driven workflow can generate consistent lesion-type labels at scale and provide an auditable basis for staging summaries to support clinician’s decisions. Future work will extend the current lesion-to-organ approach by incorporating lesion-to-lesion spatial relationships for longitudinal lesion matching and disease tracking, and by aligning outputs with . Importantly, the same spatial analysis methodology is also transferable to other TNM-staged malignancies, offering a universal tool for imaging-based classification.

Comparative bone health outcomes following tamoxifen and aromatase inhibitor therapy in breast cancer: A large-scale real-world analysis.

e12502 Background: Aromatase inhibitors (AIs) have been associated with increased bone loss and a higher risk of fractures compared to tamoxifen. This disparity is primarily attributed to differences in their mechanisms of action: in postmenopausal women, tamoxifen exhibits partial estrogen agonist effects on bone, which can lead to preservation or even improvement of bone mineral density (BMD). In contrast, AIs cause profound estrogen depletion, which accelerates bone resorption and turnover, ultimately resulting in reduced BMD and heightened fracture risk. In this study, we leveraged real-world data from the TriNetX network to compare the incidence of osteopenia, osteoporosis, and pathological fracture among patients receiving either aromatase inhibitors or tamoxifen. Methods: This TriNetX study utilized a retrospective matched cohort design using data from 157 healthcare organizations worldwide. Adult patients with breast cancer were separated into two groups: those starting tamoxifen and those starting any aromatase inhibitor (AI: anastrozole, exemestane, letrozole, or fadrozole), with the index date being the first instance of each medication after cancer diagnosis. Outcomes (osteopenia, osteoporosis, pathological fracture) were measured starting 365 days post-medication initiation. Propensity score matching ensured demographic and diagnostic balance between groups (n=120,341 per cohort). Outcomes were analyzed using association measures and Kaplan-Meier survival functions, including all patients regardless of preexisting bone conditions. Results: After matching, tamoxifen showed lower osteopenia risk (17.0% vs. 21.8%; OR 0.738, RR 0.783, p&lt;0.0001) and pathological fracture risk (2.1% vs. 2.2%; OR 0.944, RR 0.946, p = 0.0416) compared with AIs. However, osteoporosis risk was similar between cohorts (13.8% vs. 14.0%; OR 0.986, RR 0.988, p = 0.236). Ultimately, tamoxifen showed longer bone health survival overall compared to AIs (HR=0.607, p&lt;0001). These data are consistent with tamoxifen showing lower risk of BMD decreases and pathological fractures compared to AIs. Conclusions: Our large real-world cohort analysis supports other previously published evidence and meta-analyses showing a statistically significantly increased risk of osteopenia and pathological fractures with AIs when compared to tamoxifen. This reiterates the importance of bone density monitoring and addressing osteopenia before progression, especially in patients receiving endocrine therapy.