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Cancer survivorship care plans: Patients, needs, benefits—retrospective analysis.

e13793 Background: Survivorship care plans (SCPs) are designed to address the needs of cancer survivors transitioning from active treatment to long-term follow-up. They usually encompass such things as clinical surveillance, management of late and long-term effects, psychosocial support, care coordination, and financial domains. Recently, the American College of Surgeons Commission on Cancer (CoC) shifted from a defined approach to an ongoing support program model; consequently, SCPs are no longer mandatory . However, CoC Standard 4.8 mandates a Survivorship Program but formal SCPs are optional. There is a need for further research to identify and address barriers to care in the absence of formal SCPs. In 2015, Atrium Health Levine Cancer (LCI) established a formal Section of Oncology Survivorship. We describe the characteristics, unmet needs, and benefits to cancer patients referred for survivorship via SCPs. Methods: This study utilized an internal quality improvement registry. Inclusion criteria: age ≥18 years and consultation between 2015 and 2020. Patients were asked eight questions before and after their SCP encounter regarding their understanding of: 1. cancer type and stage, 2. management of current side effects, 3. possible future side effects, 4. symptoms of recurrence, 5. recurrence monitoring protocols, 6. healthy lifestyle behaviors, 7. the role of the primary care physician (PCP), 7. available emotional support resources. Responses were rated as: “completely understand”, or “do not understand”. Finally, we evaluated whether patients' baseline knowledge Pre-SCP assessments) showed significant changes or trends over the study period using univariable logistic regression. Results: We identified 1,326 patients. The mean age was 61 years (SD: ± 13); 83% female, 79% White, and 19% Black. Most were married (58%) and utilized Medicare/Medicaid (57%). Cancer types included breast (65%), gastrointestinal (8%), lung (7%), head and neck (5%), and gynecologic (4%). Thirty-eight percent earned ≤$50,000 annually, and SCPs done by advanced practice nurse in 84%. Before vs after SCP encounters, the percentage rating their understanding as "somewhat" or "do not understand" decreased significantly across all domains: Cancer type/stage: 35% → 3% Current side effect management: 56% → 5% Future side effects: 74% → 7% Recurrence symptoms: 65% → 4% Monitoring protocols: 58% → 2% Healthy behaviors: 48% → 3% Role of PCP: 50% → 3% Emotional resources: 52% → 4% Pre-SCP scores did not show any knowledge improvement over the study period. Conclusions: Baseline knowledge remained unchanged over the study period, and significant deficits remained. SCP encounters significantly improved patient understanding of their disease, self-care, and available resources. Further research is needed to identify the causes of persistent knowledge deficits and to optimize survivorship support in the absence of mandated SCPs.

Awareness of breast cancer symptoms and risk factors among urban Delhi women.

e24102 Background: Breast cancer is the most frequently diagnosed malignancy among Indian women, and late presentation continues to contribute substantially to advanced-stage disease at diagnosis. Limited knowledge of breast cancer symptoms and risk factors, along with suboptimal help-seeking behavior, represents a major barrier to early detection. Most existing Indian studies assessing breast cancer awareness have relied on non-validated assessment methods. In contrast, this study employed the Breast Cancer Awareness Measure (BCAM), a validated instrument, to evaluate breast cancer awareness and reproductive risk factors among women residing in urban resettlement communities in Delhi. Methods: Between August and October 2022, a community-based cross-sectional survey was conducted in Nandnagri, East Delhi. Women aged ≥18 years who had resided in the area for at least six months were recruited using systematic random sampling. Women with a personal or first-degree family history of breast cancer were excluded. Participants completed the validated Breast Cancer Awareness Measure (BCAM), translated into Hindi using forward–backward translation, along with a structured questionnaire assessing reproductive and lifestyle risk factors. Data were analyzed using descriptive statistics. Results: Of the 127 eligible women, 103 (81.1%) agreed, and 100 were included. The average age was 36.4 years; 78% were married, while 57% were homemakers. Breast cancer symptoms were poorly understood: only 41% recognized a painless breast lump, 32% identified new breast lumps, 28% recognized nipple discharge, and 19% identified breast size or form alterations. Only 22% had ever self-examined their breasts, and 9% did so every month. Help-seeking behavior was low, with just 14% saying that they would contact a doctor right away if they experienced any worrisome symptoms. Risk factors were also poorly understood: 29% identified family history, 24% identified rising age, and 18% recognized early menarche or late menopause as risk factors. Breastfeeding was prevalent among pregnant women (77%), with a mean duration of 46.8 months, yet only 11% were aware of its benefits. Conclusions: Breast cancer awareness in this urban resettlement community was low, with significant gaps in symptom detection, risk-factor knowledge, and appropriate help-seeking behavior. Using a validated evaluation technique yielded solid insights into community needs. Targeted educational initiatives may enhance early diagnosis and lower the burden of late-stage breast cancer in similar metropolitan areas.

Expansion of circulating NKG7⁺ cytotoxic CD4⁺ T cells as a predictor of response to PD-1 blockade in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC): A prospective phase II study with translational analysis.

6043 Background: Nivolumab has demonstrated meaningful survival benefit in patients with refractory R/M HNSCC. Nevertheless, reliable predictive biomarkers remain scarce—particularly those capable of identifying long-term survivors—underscoring the need for translational studies to uncover immune correlates of durable response. In this prospective phase II study (NCT04603248), we sought to define dynamic circulating immune cell–based biomarkers predicting durable clinical outcomes with nivolumab in patients with R/M HNSCC. Methods: Patients with R/M HNSCC who had prior failure of or intolerance to platinum-based chemotherapy were treated with nivolumab (3 mg/kg) intravenously every 2 weeks until disease progression or unacceptable toxicity occurred. Clinical outcomes were correlated with single-cell transcriptomic profiles of circulating immune cells at baseline (cycle 1 day 1) and on-treatment (cycle 2 day 1). To validate the transcriptomic findings at the protein level, mass cytometry by time-of-flight (CyTOF) analysis was additionally performed. Results: A total of 48 patients were enrolled. The objective response rate was 22.9%, and the disease control rate was 62.5%. The median progression-free survival (PFS) and overall survival (OS) were 4.4 and 13.3 months, respectively. Single-cell transcriptomic analysis revealed a significant expansion of circulating NKG7⁺ cytotoxic CD4⁺ T cells in long-term responders (PFS > 48 months; n=6) compared with early progressors (PFS < 2 months; n=6) at cycle 2 day 1. T cell receptor analysis further demonstrated that nivolumab induced marked clonal expansion of these NKG7⁺ cytotoxic CD4⁺ T cells, particularly in long-term responders. Their sustained presence was confirmed in blood samples collected one year after treatment initiation in long-term responders. CyTOF analysis (n=37) revealed that expansion of NKG7⁺ cytotoxic CD4⁺ T cells at cycle 2 day 1 was significantly associated with both PFS and OS, supporting their potential role as predictive biomarkers of response to PD-1 blockade. Conclusions: Expansion and clonal amplification of circulating NKG7⁺ cytotoxic CD4⁺ T cells represent a key immune correlate of favorable outcomes with nivolumab in refractory R/M HNSCC. These findings highlight their potential as predictive biomarkers of durable response to PD-1 blockade in R/M HNSCC and implicate this immune subset as a promising target for future immunotherapeutic strategies. Clinical trial information: NCT04603248 .

Prophylactic vedolizumab to facilitate use of immune-checkpoint inhibitors in cancer patients at high risk of immune-mediated colitis.

12134 Background: Inflammatory diarrhea/colitis is a frequent immune-related adverse event (IRAE) associated with immune checkpoint inhibitors (ICIs). Treatment with ICI is relatively contraindicated in patients with history of severe ICI-colitis or those with pre-existing severe inflammatory bowel diseases (IBD). Vedolizumab (VDZ), an anti-α4β7 integrin antibody associated with selective immune suppression in the gastrointestinal (GI) tract, is approved for IBD treatment and is also effective in treating steroid-refractory ICI-colitis. However, limited data exist for its utility as a prophylactic treatment for primary or secondary prevention of ICI-colitis in high-risk patients. Methods: We conducted a single-center, retrospective study of patients with advanced skin cancers, who were deemed “high-risk” due to prior severe ICI colitis or IBD, and received VDZ prophylaxis prior to ICI (re)treatment. VDZ efficacy was assessed by analyzing the frequency, severity, duration and treatment details of GI symptoms. In patients with prior ICI-colitis, outcomes with and without VDZ prophylaxis were compared using descriptive statistics. ICI efficacy in the presence of VDZ was evaluated by objective response rate (ORR) per RECIST v1.1. Results: We identified 16 high-risk patients (11- prior ICI colitis, 5 – IBD) who received VDZ prophylaxis (typically 300 mg at weeks 0, 2, and 6 initially, then q8 weeks) prior to ICI (re)treatment, between 2015-2025. Median number of VDZ doses before (re)introducing ICI was 2 (range, 1-3). In the ICI-colitis cohort, VDZ prophylaxis prior to ICI re-treatment resulted in less frequent and milder GI symptoms not needing corticosteroids, than previously observed with initial ICI treatment without VDZ prophylaxis (see Table). Among 14 patients with evaluable disease (measurable and progressing at the time of VDZ treatment), ORR was 33% (3/9) in the ICI-colitis cohort and 80% (4/5) in the IBD cohort. Conclusions: Use of prophylactic VDZ can facilitate successful, long-term ICI treatment in high-risk patients with prior ICI-colitis or IBD, while mitigating GI symptoms, reducing corticosteroid usage and preserving anti-tumor responses. ICI-colitis cohort, without VDZ prophylaxis (N = 11) ICI-colitis cohort, with VDZ prophylaxis (N = 11) IBD cohort, with VDZ prophylaxis (N = 5) Diarrhea (any grade), n (%) 11 (100) 3 (27) 4 Diarrhea (≥ grade 3), n (%) 8 (73) 0 2 (40) Symptom duration in days, Median (range) 75 (13, 251) 46 (8, 54) 39 (17, 129) Corticosteroid use, n (%) 11 (100) 0 2 (40) Corticosteroid use in days, Median (range) 54 (7, 102) N/A 59 (59, 59) Additional biologic therapy, n (%) 10 (91) 0 3 (60) ICI discontinuation due to diarrhea, n (%) 11 (100) 2 (18) 3 (60) ICI treatment duration in months, Median (range) 2.1 (1.4, 17.5) 7.7 (1.1, 49.0)* 7.4 (6.7, 20.8) *4 patients had ongoing ICI treatment.

Association of inpatient mortality and resource utilization with acute complications among colorectal cancer hospitalizations in the United States.

e23220 Background: Hospitalization for colorectal cancer (CRC) is frequently complicated by acute clinical events. National data describing the relative contribution of specific complications to inpatient mortality and resource utilization remain limited. Methods: A serial cross-sectional analysis was conducted using the 2018–2022 Healthcare Cost and Utilization Project National Inpatient Sample. Adult hospitalizations with a principal diagnosis of CRC were identified. Acute complications were ascertained from secondary diagnosis codes and included bowel obstruction, bowel perforation, gastrointestinal bleeding, and sepsis. 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 individual complications and in-hospital mortality, adjusting for demographics, payer, neighborhood income quartile, hospital teaching status, and calendar year. Results: From 2018–2022, 29.3% of CRC hospitalizations were complicated by at least one acute event. Bowel obstruction was the most common complication (18.9%), followed by gastrointestinal bleeding (8.9%), sepsis (3.1%), and bowel perforation (2.7%). Hospitalizations with any complication had longer LOS (10.08 vs 5.17 days) and higher mean costs ($37,106 vs $24,054) compared with uncomplicated admissions. Sepsis was associated with the greatest utilization burden (mean LOS 18.20 days; mean cost $73,304). In adjusted analyses, sepsis demonstrated the highest odds of in-hospital mortality (adjusted odds ratio [aOR] 14.23, 95% CI 12.80–15.82), followed by bowel perforation (aOR 1.84), gastrointestinal bleeding (aOR 1.44), and bowel obstruction (aOR 1.24) (all p < 0.001). Conclusions: Among CRC hospitalizations, acute complications were common and associated with substantially higher inpatient mortality and resource utilization. Sepsis, although less frequent, was associated with markedly elevated mortality and costs. These nationally representative findings provide benchmarking data on the inpatient burden associated with acute complications in colorectal cancer.

Impact of tumor site and diagnostic pathway on stage at diagnosis: A population-based study of 5,638 salivary gland cancer patients (2013–2023).

e18140 Background: Salivary gland cancer (SGC) are rare and heterogeneous malignancies. Delays in diagnosis are common and are associated with more advanced disease at presentation, increasing the risk of inoperability and of recurrent or metastatic disease following surgery. Methods: We analysed aggregated national cancer registry data (NDRS) for salivary gland cancers diagnosed in England between 2013 and 2023. Cases with known stage (TNM stages 1–4) were included. Squamous cell carcinoma of the major salivary glands was excluded. Stage at diagnosis was categorised as early (stages 1–2) or late (stages 3–4). Tumour site was grouped as major salivary glands (major) versus minor salivary glands from the head and neck (minor). Multivariable logistic regression was used to assess associations with late-stage diagnosis, adjusting for age group, sex, and route to diagnosis. Additional sensitivity analyses excluded emergency presentations and, separately, restricted analyses to planned diagnostic pathways; urgent suspected cancer pathway (USC), a fast tracked cancer specific referral pathway vs other General practitioner (GP) referrals. Results: A total of 5,638 patients with SGC were identified. Late stage at diagnosis was seen in 49.3%. Emergency presentation was strongly associated with late-stage diagnosis. In multivariable analyses adjusting for age, sex and diagnostic pathway, patients with major SGC were significantly less likely to be diagnosed at a late-stage than those with SGC of other sites (adjusted OR 0.46, 95% CI 0.46–0.47 ); this association persisted after exclusion of emergency presentations and in analyses restricted to planned diagnostic routes. Within planned pathways, patients referred via the USC pathway were significantly more likely to be diagnosed with late-stage disease compared with those referred via a GP referral (adjusted OR 1.13, 95% CI 1.12–1.13). Conclusions: In this national study of 5,638 patients diagnosed with salivary gland cancer in England over a 10-year period, stage at diagnosis was strongly associated with both tumour site and diagnostic pathway. Major salivary gland tumours were consistently less likely to be diagnosed at a late stage whereas emergency presentation was strongly associated with advanced disease. Notably, within planned diagnostic pathways, referral via the Urgent Suspected Cancer pathway was associated with a higher likelihood of late-stage diagnosis compared with GP referral, suggesting that patients meeting current USC criteria may already have clinically advanced disease at the time of referral. These findings highlight the need to optimise earlier recognition and referral of salivary gland cancers to reduce late-stage diagnosis.

Clinical and genomic characterization of de novo prostate cancer presenting with PSA ≥100 ng/mL.

e17024 Background: In the era of PSA screening for prostate cancer, presentation with PSA ≥100 ng/mL is rare. We sought to identify predictors of PSA ≥100 at diagnosis and to evaluate the prognostic role of tumor genomics in Veterans presenting with PSA ≥100 versus < 100 within the Department of Veterans Affairs (VA), where enrolled Veterans have relatively equal access to care. Methods: We conducted a retrospective cohort study of Veterans with de novo prostate cancer using the merged VA Multi-Omics Analysis Platform for Prostate Cancer and Sequencing (MAPP-SEQ) and Rate Elements Skewing Outcomes Linked to Veteran Equity in Prostate Cancer (RESOLVE PCa) databases. Veterans were included if they were diagnosed from 1999-2004 and staged in the VA Central Cancer Registry. Veterans were stratified by PSA at diagnosis ( < 100 vs ≥100 ng/mL). Among Veterans with available next-generation sequencing (NGS) performed within 6 months of diagnosis, tumors were classified into the Somatic Tumor Risk Assessment for Overall Survival-Prostate (STRATOS-P) genomic system as favorable (SPOP or no other alterations), intermediate (BRCA2, PTEN, CDK12, LYN, MYC, RAD21, CCND1, FGF19, FGF3, FGF4, AR, TP53), or unfavorable (RB1, PRCK1, FGFR1, or TP53+PTEN) gene classes (Table). We also examined metastatic sites at presentation, volume of bone metastases (mets), and sociodemographic variables. Metastatic burden across increasing PSA strata (100–200, 201–500, 501–1000, > 1000 ng/mL) was assessed. Results: A total of 273,097 Veterans with de novo prostate cancer were included, of whom 11,575 (4.4%) presented with PSA ≥100 ng/mL. No sociodemographic, rurality, service-connection, or insurance variables were independently associated with PSA ≥100 at diagnosis. Veterans with PSA ≥100 had a higher likelihood of bone mets and lower overall survival (OS) compared to Veterans with PSA < 100 (Table). In a subset of 3,020 Veterans with volume of metastatic disease data, increasing PSA was associated with higher volume disease. Among 1118 patients with NGS available, tumor gene class provided additional prognostic stratification beyond PSA alone. Unfavorable gene class demonstrated similar OS in both PSA < 100 and PSA ≥100 groups, while favorable gene class in PSA ≥100 remained inferior to PSA < 100 disease (Table). Conclusions: In a nationwide cohort of Veterans with prostate cancer, sociodemographic variables were not associated with PSA > 100 at time of presentation of prostate cancer. However, presentation with PSA ≥100 is associated with higher metastatic burden and inferior survival. Further work is needed to understand how genomic classification may refine prognosis beyond PSA. Outcome PSA <100 PSA ≥100 Mean OS (mos) 44.6 33.7 Bone mets (%) 1.7 60.2 Favorable genomics OS (mos) 51.5 36.7 Intermediate genomics OS (mos) 41.4 32.1 Unfavorable genomics OS (mos) 25.5 26.8

Baseline phosphoproteomic signatures in peripheral blood and prediction of durable response to CAR T-cell therapy in B-cell malignancies.

7038 Background: Despite the success of Chimeric Antigen Receptor (CAR) T-cell therapy, most patients fail to achieve durable remission. T-cell "fitness" is a critical, yet undercharacterized, determinant of efficacy. Standard immune and transcriptomic profiling do not measure the dynamic signaling networks driving cellular function. We hypothesized that baseline phosphoproteomic signatures in peripheral blood mononuclear cells (PBMCs) prior to CAR T-cell could serve as functional biomarkers for T-cell fitness, predicting durable response. Methods: We performed unbiased LC-MS/MS-based phosphoproteomics (KScan) on baseline PBMCs from 59 patients (39 Aggressive Lymphoma [DLBCL], 20 Multiple Myeloma [MM]) treated with CD19- or BCMA-directed CAR-T. Kinase Substrate Enrichment Analysis (KSEA) inferred upstream kinase activity. The primary endpoint was Complete Response (CR) at 6 months. We also analyzed a subset of DLBCL patients (n=6) who achieved CR at Day 30 but progressed (POD) by Month 6 ("early relapse") to identify markers of transient versus durable response. Results: We quantified 7,602 phosphopeptides. In the DLBCL cohort (20 CR, 17 POD), distinct phosphorylation in kinase signaling networks separated durable responders from non-responders, specifically implicating dysregulated stress response and MAPK signaling in resistance. KSEA revealed dysregulation in the MAPK/ERK, Casein Kinase (e.g., CSNK1E), and Cyclin-Dependent Kinase activity, linking baseline proliferative potential to long-term efficacy. Notably, the "early relapse" group (Day 30 CR / Month 6 POD) exhibited a unique profile, characterized by differential phosphorylation of proteins involved in apoptotic regulation and chromatin remodeling (e.g., FADD, ARID1A, ACIN1, KMT2A), suggesting these intrinsic defects may limit CAR T-cell persistence. Correlation analysis further integrated these signaling features with CD3+, CD4+, and CD8+ T-cell counts, validating their biological relevance. In the MM cohort, the signaling landscape was heavily dominated by immune cell composition. KSEA revealed that kinase activity in CR patients strongly correlated with the CD4:CD8 ratio and absolute CD3+ counts, validating that the captured phosphoproteomic variance reflects the underlying T-cell phenotype required for successful expansion and cytotoxicity. Conclusions: Baseline PBMC phosphoproteomics is a powerful tool for predicting CAR T-cell efficacy. We identified specific signatures—distinct from broad immune cell counts—that differentiate durable responders from patients at risk of primary refractory disease or early relapse. These targets highlight avenues for pharmacological conditioning to enhance T-cell fitness. These data support integrating functional proteomic biomarkers into patient stratification strategies to optimize outcomes.

Multimodality neoadjuvant downstaging therapy before liver transplantation for colorectal liver metastasis: Real-world data from the Cleveland Clinic.

3594 Background: Liver transplantation (LT) has a clear survival benefit in advanced, unresectable, liver-confined colorectal cancer liver metastasis (CRLM). However, pre-transplant management and optimal selection criteria remain understudied and previously reported data indicate recurrence-free survival <40% at 3- and 5-years post-LT. Methods: 23 patients entered the protocol; 22 patients underwent LT (12/2017-12/2025) utilizing the Cleveland Clinic protocol for down-staging prior to LT. The protocol involves intensive locoregional therapy (LRT) with systemic chemotherapy, aiming to reach minimal disease burden based on FDG PET-CT, ctDNA, and CEA. Patients with minimal or no detectable disease or irreversible treatment-induced liver injury undergo transplant. Patients must have disease control for at least 1 year after resection of the primary colorectal tumor. Results: Median age at LT was 45 years (IQR=39-50). Median largest tumor size on pre-LT imaging was 2.2 cm (1.6–7.35), and 18 patients (82%) had bilobar disease. Most patients received intensive systemic therapy (median=18 cycles, IQR=12-37), including 5-FU (n=18), oxaliplatin (n=18), irinotecan (n=13), and bevacizumab (n=17). Tumors were KRAS (n=6) and BRAF non-V600E (n=2) mutated. 20 patients (91%) received pre-LT LRT, including radioembolization (n=11), ablation (n=9), resection (n=10), and HAI pump (HAIP) (n=7). Only one patient dropped out of the pre-LT protocol for liver failure in 2017, suspected from combination of bilobar Y90 and SBRT. Pre-LT PET showed metabolic activity in 8 patients (36%). Median PET-Metabolic Tumor Volume (MTV) at protocol entry was 49.2cm 3 (18-162) and at LT was 0cm 3 (0-6.4) with a median MTV-reduction of 45.2cm 3 (18-156). Median MELD-Na at LT was 9 (IQR 6–13). Pre-LT tumor agnostic ctDNA was detected in 12/17 patients (71%). All patients with ctDNA(-) pre-LT had non-viable tumor on explant (n=5/5 vs. ctDNA(+)=5/12, p=0.028). At median follow-up of 1.6 years, 20 (91%) remain alive, and 18 (82%) are recurrence-free. Median RFS was 5.4 years (95%CI=3.52-7.36) and OS=6.72 years (95%CI=5.34-8.00). Recurrences were lung (n=2), liver (n=1), and liver+para-aortic (n=1) nodes. There was no post-LT recurrence when non-viable on PET scan and on histology (log-rank p<0.001). Pre-LT PET-MTV>70cm 3 correlated with histologically viable tumor (p=0.031). Pre-LT HAIP demonstrated a trend towards non-viable tumor on explant (n=5/7 non-viable, 71%). Conclusions: LT for CRLM shows clear survival benefit in randomized trials. Aggressive pre-LT locoregional and systemic therapies aimed at minimizing disease burden assessed by PET scan and ctDNA may demonstrate improved outcomes, as may HAIP. A clinical trial testing these hypotheses has been designed with expected enrollment in 2026 at three sites.

Comprehensive profiling of EGFR PACC mutations and their co-mutation landscape in Chinese patients with non–small cell lung cancer: A large-scale NGS study of 2,360 cases.

8650 Background: EGFR PACC (P-loop and αC-helix compressing) mutations represent a group of noncanonical alterations located in critical structural regions of the EGFR kinase domain and have recently been implicated in reduced sensitivity to EGFR TKIs and treatment resistance. However, the prevalence, mutational spectrum, and co-mutation landscape of EGFR PACC mutations in Chinese patients with non–small cell lung cancer (NSCLC) remain poorly characterized. This study aimed to systematically delineate the molecular features of EGFR PACC mutations to inform molecular testing strategies and clinical decision-making. Methods: A total of 2,360 patients with NSCLC were enrolled. All tumor samples underwent NGS covering 733 cancer-related genes. The overall prevalence of EGFR PACC mutations, the distribution of individual PACC variants, and their co-occurrence with other EGFR alterations and non-EGFR driver mutations were comprehensively analyzed. Results: Among the 2,360 NSCLC patients, 112 harbored EGFR PACC mutations, yielding an overall prevalence of 4.74%. EGFR PACC mutations exhibited marked site heterogeneity. The most frequent variants were S768I (18/112), G719A (15/112), G719S (12/112), and G719C (8/112), followed by C797S (6/112), E709A (6/112), E709V (5/112), and E709K (5/112). The remaining PACC variants—including I740_K745dup, R776H, S752_I759del, V774M, E709_T710delinsD, G779F, K757R, L747P, L718V, R776C, A647T, K757M, L718Q, T751_I759delinsN, V769L, and V769M—were low-frequency events, underscoring substantial molecular diversity. In total, 61 PACC-associated co-mutation events were identified. Co-mutation analysis revealed that classic EGFR-sensitizing mutations predominated, with L858R as the most common co-occurring alteration (n = 10), followed by exon 19 deletion E746_A750del (n = 4) and L861Q (n = 3). Notably, T790M (n = 2) co-occurred with C797S PACC mutations, suggesting a potential role of PACC variants in the evolution of EGFR-TKI resistance. Beyond EGFR-intrinsic co-mutations, cross-driver co-mutations were also observed, including ROS1 (V1002A, I1685L), MET (V145A), and NRG1 (V516M) (each n = 2), indicating that a subset of EGFR PACC–mutant tumors may harbor more complex oncogenic signaling. Conclusions: EGFR PACC mutations occur at a non-negligible frequency in Chinese patients with NSCLC and display pronounced site heterogeneity. These mutations frequently co-exist with classic EGFR-sensitizing or resistance-associated alterations and, in some cases, with additional non-EGFR driver mutations, highlighting their potential biological and clinical relevance. Our findings underscore the importance of comprehensive NGS-based profiling for accurate detection of EGFR PACC mutations and their co-mutation landscape, thereby supporting precision treatment strategies.

Allostatic load as a mediator of exposomic risk pathways to early-onset cancer: A cross-cohort validation study.

10500 Background: Early-onset cancer (EoC, defined as any solid tumor diagnosed ≤50 years age) incidence has increased 79% globally since 1990. Traditional risk models focus on isolated exposures or specific rare genetic variants and have limited utility for EoC, as high-penetrance mutations account for <10-20% of cases depending on tumor type. Allostatic load (AL) – the cumulative physiological burden of chronic stress across neuroendocrine, immune, and metabolic systems – may represent a pan-EoC mechanism linking environmental exposures to EoC carcinogenesis. Methods: We analyzed 13,745 adults aged ≤50 years (2,749 EoC cases) across two population-based cohorts: UK Biobank (UKB; n=5,100) and NIH All of Us Research Program (AoU; n=8,645). AL was constructed by summing standardized indicators for 8-11 baseline biomarkers representing cardiovascular (blood pressure), metabolic (HbA1c, glucose, cholesterol, BMI), and immune (CRP, WBC, albumin) domains. An exposome score was derived via bifactor analysis of 61 (UKB) and 11 (AoU) baseline exposures spanning diet, lifestyle, neighborhood, and psychosocial factors. Propensity score matching controlled for age, sex, race/ethnicity, and socioeconomic indicators. Mediation analysis estimated indirect effects of exposome on EoC operating through AL. Results: Mean age was 43.0 years in UKB and 39.8 years in AoU; 72.5-76.5% were female. For each SD increase in baseline AL, there was 11-18% increased odds of subsequent EoC (AoU OR: 1.18 [95%CI 1.12-1.24]; UKB OR: 1.11 [1.04-1.18]). Exposome score was significantly associated with AL (AoU β=0.09; UKB β=0.08; both p<0.001). Mediation analyses revealed significant indirect effects in both cohorts, with non-significant direct effects (Table). For exposome-related cancers, AL mediated 8.7-15.4% of exposomic risk. Conclusions: This is the first multinational population-level study to demonstrate that AL mediates environmental risk pathways to EoC, supporting the hypothesis that cumulative environmental burden promotes carcinogenesis through physiological stress pathways. AL represents a potentially modifiable target for EoC risk stratification. Future research integrating polygenic risk and longitudinal exposome assessments may refine mechanistic understanding and enable precision prevention approaches for this growing public health challenge. Mediation of exposome-EoC association via AL. Cohort Cancer Group Indirect Effect* (p) Direct Effect # (p) Proportion Mediated (p) AoU All 0.005 (<0.001) −0.012 (0.14) − AoU Exposome-Related 0.001 (<0.001) 0.007 (0.06) 15.4% (0.02) UKB All 0.002 (<0.001) −0.005 (0.63) − UKB Exposome-Related 0.001 (0.01) 0.008 (0.17) 8.7% (0.14) *β of exposome-EoC effect operating through AL. # β of exposome-EoC effect independent of AL. Exposome-related cancers: colorectal, lung, liver, bladder, upper GI.

Alternative splicing signatures to predict response from hyperthermic intra-peritoneal chemotherapy (HIPEC) treatment in ovarian cancer patients.

e17576 Background: HIPEC is associated with improved survival in epithelial ovarian cancer (EOC) patients, but no predictive biomarkers exist to guide optimal patient selection. Alternative splicing events (ASEs) have demonstrated prognostic value in multiple cancers, including EOC. We set out to identify response-associated ASEs as potential predictive biomarkers associated with HIPEC response in EOC patients. Methods: Ninety-one EOC patients who underwent HIPEC (2014-2022) with available pre-operative tumors at COH and CHU were identified. RNA was isolated from formalin-fixed paraffin-embedded samples, and whole-transcriptome libraries constructed. HIPEC response was defined by the following progression-free survival (PFS) cut-off values to distinguish good vs poor responders: 18 months in primary EOC patients (based on KGOG, CARCINO-HIPEC trials), and 12 months in recurrent EOC patients (based on MSK, CHIPOR HIPEC trials). We performed splice analysis using SplAdder and Bisbee to detect and quantify alternative splicing events (ASEs) from short read RNA-seq data from tumors. Significantly differentially ASEs between poor vs good responders were determined using Log-Likelihood Ratio (LLR), in Bisbee. MHC class I binding prediction of potential neopeptides generated by ASEs were computed using NetMHCpan. Results: A total of 56 EOC tumor samples were analyzed, after exclusion of 35 samples due to quality control or missing data. 57.1% were primary EOC, 42.9% recurrent EOC. Median follow up was 37.6 mo.; median PFS was 29.3 mo. in primary EOC and 26.0 mo. in recurrent patients. Good responders (n=39) had lower PCI, lower recurrence, and longer OS (95%CI: 47.9, NR), compared to poor responders (n=17), (95%CI: 24.1, NR). For the entire cohort, we identified 228 ASEs, of which 89 were predicted to produce a novel non-canonical protein sequence predominantly due to intron retention events (~80%). Thirty-six protein coding ASEs were significantly increased in good responders (LLR>20), with significantly positive enrichment in transcripts from Dead-Box family RNA Helicases (DDX5, DDX41, DDX27 and DDX3X), known to participate in RNA processing. By further selecting down ASEs with LLR>20 and Percent Spliced In (PSI) threshold of >5%, we retained 11 ASEs predicted to produce strong binders against MHC class I, including events in Serine/Arginine-Rich Splicing Factor 5 (SRSF5), a key protein involved in mRNA splicing. Conclusions: Alternative splicing analysis of RNA-Seq data from treatment naïve EOC tumors identified candidate protein coding ASE signatures involving the DDX family of RNA helicases to be associated with good response to HIPEC. Future plans include the development of a robust multi-panel ASE classifier expansion in a larger independent patient cohort to establish predictive treatment stratifications in HIPEC.

Integration of a diabetes practitioner in breast cancer care and its impact on glucose management.

e23064 Background: Dysglycemia in breast cancer patients is associated with poor cancer outcomes and increased emergency department (ED) and hospital utilization, often necessitating treatment modifications. Given the complexity of breast cancer management, streamlined care is essential to support patients in effectively managing comorbid conditions. Accordingly, we evaluated whether integrating a diabetes practitioner into a breast cancer clinic improves glycemic outcomes. Methods: We conducted a retrospective chart review of breast cancer patients at Parkland Health (Dallas, TX) who received care from an integrated diabetes practitioner for dysglycemia management. Patients who established care with the practitioner between March 1, 2021 and August 31, 2025 and were followed for more than three months were included. Hemoglobin A1c (HgbA1c) values were retrieved at cancer diagnosis, at the first diabetes visit, and at the time point closest to the end of the study period. HgbA1c values at the first diabetes visit and at study end were compared using a two-tailed t-test. Secondary variables included breast cancer subtype, stage at diagnosis, ED or hospital utilization for dysglycemia after the first diabetes visit, and cancer treatment status. IRB approval was obtained prior to study implementation (ID STU20250209). Results: Twenty-one patients met the inclusion criteria. The most common breast cancer subtype was invasive ductal carcinoma, with a median stage of IIA at diagnosis. Median follow-up with the diabetes practitioner was 1.98 years. Mean HgbA1c at cancer diagnosis was 8.7%. Mean HgbA1c decreased from 8.4% at the first diabetes visit to 7.3% at study end (p = 0.02). No patients required ED or hospital visits for diabetes-related complications after the first diabetes visit. During follow-up, 12 patients transitioned from active cancer treatment to survivorship, with a median survivorship duration of 8.67 months. One patient died from breast cancer–related complications. Conclusions: Integration of a diabetes practitioner into a breast cancer clinic was associated with significant improvements in glycemic control and the absence of diabetes-related ED or hospital utilization. Improved glycemic control may reduce acute care needs during active cancer treatment and could facilitate more consistent cancer therapy delivery, potentially contributing to improved cancer outcomes and progression to survivorship. Embedding diabetes management within oncology clinics may represent a scalable strategy to improve outcomes and support longitudinal care for breast cancer patients with comorbid dysglycemia.

Safety and reliability of isatuximab subcutaneous on-body injector: Results across the phase 3 IRAKLIA, phase 2 IZALCO and phase 1b TCD15484 trials.

7563 Background: Subcutaneous (SC) drug delivery options have become more widely available in multiple myeloma (MM). SC delivery of isatuximab (Isa), an anti-CD38 monoclonal antibody, has been investigated across clinical trials via a novel hands-free on-body injector (OBI). Isa SC OBI features a small, retractable needle, establishing the first device-enabled delivery of an oncologic treatment. The Phase 3 IRAKLIA, Phase 2 IZALCO, and Phase 1b (TCD15484) trials consistently demonstrated similar efficacy and safety of Isa SC OBI vs Isa IV in relapsed/refractory MM (RRMM) patients (pts). Here, we present a cross-trial analysis exploring safety and reliability of Isa SC OBI in RRMM pts. Methods: Pts with RRMM in IRAKLIA (N=263) and the Phase 1b expansion cohort (N=22) received 1400 mg Isa SC OBI plus pomalidomide and dexamethasone (d). In IZALCO, RRMM pts (N=64) received 1400 mg Isa SC OBI + carfilzomib (K)-d. Pts were monitored for 4 hrs (IRAKLIA) or 1-2 hrs (IZALCO) following first administration and for 1 hr for the following cycle (C) 1 administrations to assess local tolerability. Pre-infusion medications included montelukast (C1), steroids, acetaminophen and H1 antihistamines. Pts without systemic infusion-related reactions (IRRs) after 4 consecutive administrations of Isa SC OBI had subsequent pre-medication reassessed at investigator’s discretion. Safety and device performance explored in this cross-trial analysis of company sponsored studies were assessed in the Isa SC OBI cohorts by the duration of injection, IRRs, local injection-site reactions (ISRs), and injection/device success, which were defined similarly across all trials. Results: The median duration of Isa SC OBI injection was 13 mins in IRAKLIA, 12 mins in IZALCO, and 10 mins in the Phase 1b trial (6426 total injections, N=349 pts). IRRs across trials occurred in 6/6426 (0.09%) injections and 4/349 (1.15%) pts. IRRs were mostly grade 1 (G; 3/6426, 0.05%) with 1 G3 (0.02%); none leading to discontinuation. In IRAKLIA, 80/263 (30.4%) pts did not require premedication (931/5145 injections, 18.1%); no IRRs occurred in this group. Across trials, ISRs occurred in 21/349 (6.02%) pts resulting in 35 (0.54%) ISR events. Most ISRs were G1 (33, 0.51%), the remaining were G2 (2, 0.03%) and generally occurred on the day of injection. 99.9% (6421/6426) of injections in 98.6% (344/349) pts were successful (completed without interruption) across all trials. Conclusions: These findings support overall low, self-limiting rates of IRRs and ISRs across trials, with >6000 (99.9%) Isa SC OBI injections successfully delivered. Isa SC OBI shows reproducible safety and reliability in IRAKLIA, IZALCO and Phase 1b trials, supporting it as a novel administration option for MM pts and its potential for future exploration in at-home administration. Clinical trial information: NCT04045795 , NCT05405166 , and NCT05704049 .

A novel ultra-low 6-month PSA cutoff for radiographic PFS stratification in high-volume mHSPC.

e17099 Background: In metastatic hormone-sensitive prostate cancer (mHSPC), a 6-month PSA nadir ≤0.2 ng/mL is commonly applied as an early prognostic benchmark. Moreover, routine PSA reporting is often truncated at low values (e.g., < 0.1–0.2 ng/mL), limiting assessment of deeper PSA responses. Therefore, using ultrasensitive PSA measurements, we aimed to identify a novel ultra-low 6-month PSA nadir cutoff that better discriminates rPFS in high-volume mHSPC. Methods: A total of 159 patients with CHAARTED-defined high-volume mHSPC were included. The primary endpoint was rPFS; a 6-month landmark was used to mitigate immortal time bias. The optimal 6-month PSA cutoff for rPFS discrimination was identified using maximally selected rank statistics with log-rank testing across candidate thresholds, with multiplicity-adjusted p-values (R). rPFS was estimated by Kaplan–Meier, and hazard ratios were derived from univariable Cox regression. Results: Median age was 69.3 years (IQR 63.2-74.6), median baseline PSA was 100.5 ng/mL (IQR 25.6-306.3), and median follow-up was 32.8 months (IQR 20.2–44.7). Using maximally selected rank statistics, the optimal 6-month PSA cutoff was identified as 0.07 ng/mL. At month 6, 55/159 patients (34.6%) achieved PSA ≤0.2 ng/mL and 32/159 (20.1%) achieved PSA ≤0.07 ng/mL. Patients with PSA ≤0.07 ng/mL had significantly longer rPFS (median not reached vs 20.3 months; progression events 2/32 vs 84/127; log-rank p < 0.001). Compared with PSA ≤0.07 ng/mL, PSA > 0.07 ng/mL was associated with higher risk of radiographic progression (HR 14.27; 95% CI 3.51–58.05; p < 0.001). Conclusions: In high-volume mHSPC, the conventional 6-month PSA threshold of 0.2 ng/mL may be insufficient to capture the highest-risk patients. Our study identifies an optimal "ultra-low" cutoff of 0.07 ng/mL that provides superior prognostic discrimination for rPFS. Achieving PSA ≤0.07 ng/mL is associated with markedly superior outcomes, whereas PSA > 0.07 ng/mL identifies a population at imminent risk of radiographic progression. This deeper PSA response provides a pragmatic candidate threshold for assessing treatment efficacy and for risk stratification in high-volume disease, warranting validation in larger, well-designed studies. Baseline characteristics of the study population. Characteristic Overall population (n=159) Age, median (IQR), years 69.3 (63.2–74.6) ECOG performance status 0 69 (43.4%) ≥1 90 (56.6%) Metastatic status at diagnosis De novo 135 (84.9%) Recurrent 24 (15.1%) Visceral metastasis Yes 51 (32.1%) No 108 (67.9%) Charlson Comorbidity Index (CCI) Median (range) 3 (0–12) CCI <3 70 (44.0%) CCI ≥3 89 (56.0%) Baseline laboratory parameters ALP Normal Elevated 67 (42.1%)79 (49.7%) LDH Normal Elevated 68 (42.8%)72 (45.3%) PSA, median (range), ng/mL 100.5 (25.6-306.3) Systemic therapy ADT alone 39 (24.5%) ADT + ARPI 76 (47.8%) ADT + docetaxel 44 (27.7%)

Spatially Proximate Acid Sites in Zeolites Synergistically Boost Alkane Activation

ABSTRACT The activation of light alkanes on zeolites has long been attributed to strong Brønsted acid sites (BAS), a focus that has constrained further catalyst development. Here, we report that in steamed ZSM‐5 zeolites, B 2 sites from partial hydrolysis of framework aluminum cooperate with neighboring classical BAS (B 1 ) to establish a proximate acid‐site microenvironment that substantially enhances both alkane adsorption and activation. Combining solid‐state NMR, in situ FTIR spectroscopy with two‐dimensional correlation analysis, and density functional theory calculations, we demonstrate that the neighboring B 1 /B 2 sites exhibit a stronger intrinsic affinity for propane than isolated B 1 sites, accelerating its accumulation within the pores, which is attributable to the locally optimized van der Waals interactions tuned by the Al─OH of B 2 . The resulting cooperative acid sites synergistically entrap alkane molecules and facilitate C─H bond activation, boosting propane conversion from 27.2% to 37.5%. Our findings reveal a mechanism for alkane activation that is driven by proximate acid‐site cooperativity rather than conventional acid strength of isolated BAS, opening an avenue for designing efficient zeolite catalysts via microenvironment engineering.

Engineered CuO nanoparticles: A multifunctional platform for corrosion resistance, photocatalysis, and antibacterial activity

Electron‐Deficient Single‐Molecule‐Junction Sites in COFs Enable H ₂ O ₂ Photosynthesis via Precision Charge Delivery and Oxygen Adsorption

ABSTRACT Covalent organic frameworks (COFs) have emerged as a promising platform for photocatalytic H 2 O 2 production, a key reaction in artificial photosynthesis. However, the practical application of conventional benzene‐rich COF skeletons is often limited by their weak oxygen adsorption capacity and inefficient charge carrier transport. To address these challenges, we report a universal post‐synthetic strategy that incorporates local, electron‐deficient polar single‐molecule junctions into the COF framework via a straightforward one‐step modification. These engineered junctions play a dual role: the localized electron‐deficient sites strongly anchor and activate oxygen molecules, while the in‐built polarity establishes directional channels for the migration of photogenerated charge carriers, ensuring their precise delivery to active sites. This synergistic mechanism leads to a marked enhancement in superoxide radical generation and the subsequent synthesis of H 2 O 2 . Under acidic conditions (pH = 3), the H 2 O 2 generation rate of the monomolecularly‐linked COF reached 4354 µmol g −1 h −1 , significantly higher than the 1655 µmol g −1 h −1 of the pristine COF. The broad applicability of this design principle was firmly established through the successful implementation of a series of tailor‐made analogous molecules across several distinct COF platforms.

Comparative serious safety reporting signals for antibody-drug conjugates versus HER2-targeted non-ADC therapies: A FAERS analysis (2020–2025).

e13084 Background: Antibody–drug conjugates (ADCs) have transformed systemic cancer therapy but are associated with distinct and potentially severe toxicities. Post-marketing pharmacovigilance databases such as the FDA Adverse Event Reporting System (FAERS) enable detection of rare or serious adverse event (AE) reporting signals but do not permit incidence estimation or causal attribution. Comparative real-world safety data across ADCs remains limited. Methods: We performed a retrospective pharmacovigilance analysis of serious FAERS reports (2020–2025), comparing sacituzumab govitecan, trastuzumab deruxtecan, trastuzumab emtansine, and datopotamab deruxtecan with HER2-targeted non-ADC therapies analyzed as a composite reference. Analyses focused on prespecified pulmonary, cardiac, and gastrointestinal toxicities; other toxicities were not comprehensively evaluated. Disproportionality was assessed using reporting odds ratios (RORs) with 95% confidence intervals. Death was analyzed as a reported outcome with age stratification; FAERS does not permit attribution to drug exposure or disease progression. Results: Among serious reports, T-DXd showed the strongest pulmonary safety signals, including interstitial lung disease (ROR 12.86, 95% CI 11.20–14.76) and pneumonitis (ROR 8.16, 95% CI 6.83–9.76). T-DM1 demonstrated moderate pulmonary signals and a cardiac signal for left ventricular dysfunction (ROR 1.92, 95% CI 1.43–2.57). SG was characterized by prominent gastrointestinal toxicity, with diarrhea as the most frequently reported serious GI event (ROR 1.01), while pneumonitis showed elevated disproportionality despite lower frequency (ROR 2.34). Death was disproportionately reported across ADCs versus HER2-targeted non-ADC therapies, with elevated signals for Dato-DXd (ROR 4.78), T-DXd (ROR 2.97), SG (ROR 2.24), and T-DM1 (ROR 1.28). Age-stratified analyses showed comparable or higher death disproportionality among patients < 40 years versus ≥40 years. Conclusions: ADCs exhibit distinct serious safety reporting profiles compared with HER2-targeted non-ADC therapies, with prominent pulmonary signals for T-DXd and GI toxicity for SG. Reported death disproportionality likely reflects the severity and treatment-refractory nature of the populations rather than drug-attributable mortality and should be interpreted cautiously, given the limitations of FAERS. This focused, hypothesis-generating analysis underscores the importance of vigilant toxicity monitoring and highlights the need for complementary real-world and prospective studies incorporating clinical context, broader toxicity characterization, and causal attribution.

Indirect calorimetry and estimated energy prescription in hospitalized cancer patients.

e23335 Background: Indirect calorimetry is recommended as the reference method for individualized energy prescription in patients with cancer; however, fixed weight-based caloric targets remain widely used in routine clinical practice. This study evaluated how commonly prescribed targets of 35 and 50 kcal/kg/day compare with measured resting energy expenditure (REE) in hospitalized oncology patients. Methods: A retrospective analysis of consecutive indirect calorimetry measurements performed in an oncology and hematology inpatient ward between February 12, 2024, and October 21, 2025, was conducted. Resting energy expenditure was recorded in kcal/day and normalized per kilogram of measured body weight. Empirical caloric targets of 35 and 50 kcal/kg/day were simulated for each measurement. Agreement with measured REE was assessed using mean bias, percent error, and the proportion of estimates within ±10% of measured expenditure. Results: Fourteen indirect calorimetry measurements were analyzed. Mean body weight was 61.8 ± 9.7 kg, and mean measured REE was 1626.9 ± 279.4 kcal/day, corresponding to 26.9 ± 6.2 kcal/kg/day. A target of 35 kcal/kg/day overestimated measured REE by a mean of 537 ± 444 kcal/day, with a mean percent error of 36.3%. Only 28.6% of estimates were within ±10% of measured REE, while 71.4% exceeded measured expenditure by more than 20%. A target of 50 kcal/kg/day resulted in marked overestimation, with a mean bias of 1464.9 ± 564.9 kcal/day and a mean percent error of 94.7%. No estimates using 50 kcal/kg/day were within ±10% of measured REE, and 85.7% exceeded measured expenditure by more than 50%. Conclusions: In this real-world inpatient oncology cohort, measured resting energy expenditure clustered around 27 kcal/kg/day. Fixed caloric prescriptions of 35 kcal/kg/day frequently overestimated energy needs, while 50 kcal/kg/day led to substantial and systematic overfeeding. These findings support the use of indirect calorimetry when feasible and highlight the risks associated with high empirical calorie targets in hospitalized patients with cancer. Key findings from indirect calorimetry, n = 14. Metric Value Weight, kg 61.8 ± 9.7 Measured REE, kcal per day 1626.9 ± 279.4 Measured REE, kcal per kg per day 26.9 ± 6.2 Bias of 35 kcal per kg per day target, kcal per day +537 ± 444 Within ±10 percent of REE using 35 kcal per kg per day 28.6 percent Bias of 50 kcal per kg per day target, kcal per day +1464.9 ± 564.9 Within ±10 percent of REE using 50 kcal per kg per day 0 percent REE = resting energy expenditure. Bias represents prescribed minus measured energy expenditure.